Low-Dose Doxepin Formulations And Methods Of Making And Using The Same

ABSTRACT

The invention disclosed herein generally relates to low-dose oral doxepin pharmaceutical formulations and the use of these formulations to promote sleep.

INCORPORATION BY REFERENCE TO RELATED APPLICATIONS

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57.

FIELD

Embodiments of the invention disclosed herein relate to low-dose oraldoxepin pharmaceutical formulations, methods of making the formulations,and the use of these formulations to promote sleep.

BACKGROUND

Low doses of doxepin can be used to treat sleep disorders, such asinsomnia. Sleep is essential for health and quality of life. Insomnia isa growing health problem in the United States. It is believed that morethan 10-15 million people suffer from chronic insomnia and up to anadditional 70 million people suffer from some form of insomnia eachyear. Insomnia is a condition characterized by difficulty falling asleep(sleep onset), waking frequently during the night (fragmented sleep),waking too early (premature final awakening), and/or waking up feelingun-refreshed. In the National Sleep Foundation's (NSF) Sleep in AmericaPoll 2005, 42% of survey respondents reported that they awoke frequentlyduring the night, 22% of adults reported waking too early and not beingable to return to sleep and 38% reported waking and feelingun-refreshed.

Doxepin is a tricyclic compound currently approved for treatment ofdepression or anxiety at a daily dose of 75 mg to 300 mg. Non-liquidforms of doxepin are currently available in 10, 25, 50, 75, 100 and 150mg capsules. Liquid concentrate doxepin is available in a dosage of 10mg/mL. It should be noted that some embodiments can specifically excludeformulations of doxepin in capsule form, in particular capsules with apowder therein. Capsules with 10 or more mg of doxepin can be excludedfrom some embodiments. Also, gelatin coated capsules with or without apowder therein can be excluded from some embodiments. Methods oftreating sleep using 10 mg capsules or drug taken (e.g., taking afraction of the powder from the capsule) or derived (e.g., dilutingmaterial from a capsule prior to taking) from 10 mg capsules can bespecifically excluded from some embodiments.

Making low dose formulations can present technical and economicchallenges that are not present for higher dose formulations.Furthermore, existing doxepin formulations do not take into account theunique aspects of sleep disorders.

Embodiments of the invention provide low dose formulations of doxepinand doxepin compounds, and also address and overcome the challenges andproblems associated with formulating and manufacturing low-dose doxepindosage forms.

SUMMARY

Embodiments of the invention disclosed herein relate to low dose doxepinformulations. Also, some embodiments relate to manufacturing processesfor the formulations, as well as methods of using the formulations. Insome aspects the formulations have one or more desirable physicalproperties, have preferable functional characteristics, and/or permitefficient and economical manufacturing of low dose doxepin dosage forms.

In the development of pharmaceutical dosage forms, it can be desirableto achieve any of several different objectives. For example, preferablythe dosage form can be uniform with respect to drug substance content,fast dissolving, stable, easy to swallow, palatable, and otherwiseacceptable to patients in order to maximize patient compliance. Incertain contexts, early and/or accelerated onset of drug action also canbe advantageous. For example, in the context of sleep, early onset ofdrug action can be important due to the discreet window of time in whicha patient needs to sleep. Also in the context of sleep, the dosage formpreferably maintains sleep for a full 7 or 8 hour sleep cycle withoutsignificant next-day sedation.

Additionally, it may be desirable to have a manufacturing process thatis economical, efficient, robust, and preferably, simple-requiring aminimal number of steps and/or excipients. Furthermore, the activeingredient and excipients preferably have suitable flow properties toensure efficient mixing and acceptable content uniformity, weightuniformity, hardness, and friability of the final dosage form. Good flowproperties also may be beneficial for precise volumetric feeding of thematerial to a die cavity. However, efficient mixing and acceptablecontent uniformity are difficult to achieve for low dose dosage forms.

Mixed particle sized powders can segregate due to operationalvibrations, resulting in final dosage forms with poor drug or activepharmaceutical ingredient (API) content uniformity. Active substanceswith a small particle size mixed with excipients having a largerparticle size will typically segregate or de-mix during the formulationprocess. The problem of small particle size and poor flowability can beaddressed by enlarging the particle size of the active substance,usually by granulation of the active ingredient either alone or incombination with a filler and/or other conventional excipients.Granulation processes may be energy intensive unit operations requiringcomplicated and expensive equipment as well as technical skill.

Extensive laboratory and full-scale research have resulted in a new andinventive process for directly compressing low-dose doxepin dosageforms. Accordingly, embodiments of the invention disclosed hereinaddress and achieve one or more of the above-mentioned considerations.Some embodiments surprisingly achieve several or many of theconsiderations.

In particular, embodiments disclosed herein relate to pharmaceuticaldosage forms comprising low doses of doxepin hydrochloride, methods ofmanufacturing low-dose doxepin dosage forms, and methods of using theformulations and dosage forms. Preferably, the low doses of doxepinhydrochloride can be provided as rapidly dissolving dosage forms, asdescribed herein, which can be advantageously used for treatment ofinsomnia. In some aspects, the formulations have one or more of:improved friability, compression, dissolution, uniformity,dissolvability, palatability, and the like. Also, in some aspects, theformulations can permit at least one or more of: rapid onset, greaterand/or more rapid plasma levels, and the like.

Additional embodiments disclosed herein relate to new and economicmethods of manufacture for low-dose dosage forms of doxepin, including,for example, on a large scale. In a preferred embodiment, the methods ofmanufacture can achieve uniformity of drug substance content andovercome segregation issues that can plague low dose formulations, andcan do so in an economical and efficient manner. Some embodiments of theinvention relate to low dose doxepin formulations that are amenable todirect compression and that produce a high yield of low dose doxepindosage forms having acceptable content uniformity, hardness, andfriability.

Thus, embodiments of the invention disclosed herein relate topharmaceutical compositions comprising from about 0.5 to about 9 mg ofdoxepin, or a pharmaceutically acceptable salt or prodrug thereof, andfrom about 20% to about 99.9% w/w silicified microcrystalline cellulose.In one embodiment, silicified microcrystalline cellulose (SMCC) can beprovided in an amount of about 92% to about 99.8% w/w. The compositionscan further comprise from about 0.1 to about 1.5% w/w colloidal silicondioxide. In another embodiment, the compositions further comprise fromabout 0.25 to about 1.5% w/w magnesium stearate. In another embodiment,doxepin can be provided in an amount of about 0.8 mg to about 2 mg orabout 1 to about 2 mg. In yet another embodiment, doxepin is provided inan amount of about 1 mg. SMCC can be provided in an amount of about98.5% w/w. In one aspect, doxepin is provided in an amount of about 2.5mg to about 4 mg or about 3 to about 4 mg. In another aspect, doxepin isprovided in an amount of about 3 mg. In one embodiment, SMCC is providedin an amount of about 96.7% w/w. In another embodiment, doxepin isprovided in an amount of about 5.5 to about 7 mg or about 6 to about 7mg. In one aspect of this embodiment, doxepin is provided in an amountof about 6 mg. In another embodiment, SMCC is provided in an amount ofabout 94% w/w. The compositions disclosed herein can be in the form of atablet, a film coated tablet, a capsule, a gel cap, a caplet, a pellet,a bead, or the like. In one embodiment, the compositions are in the formof tablets. In another embodiment, the compositions preferably are inthe form of film coated tablets. In another embodiment, the compositionseach have a total weight of about 50 mg to about 500 mg. In one aspectof this embodiment, the compositions each have a total weight of 50 mg,75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, or the like. In one embodiment, the compositions each have atotal weight of about 150 mg.

Embodiments of the invention also can include pharmaceuticalcompositions comprising from about 0.5 to about 9 mg of doxepin, or apharmaceutically acceptable salt or prodrug thereof, and at least onefiller. In one embodiment, the filler can be, for example, silicifiedmicrocrystalline cellulose, microcrystalline cellulose, lactose, acompressible sugar, xylitol, sorbitol, mannitol, pregelatinized starch,maltodextrin, calcium phosphate dibasic, calcium phosphate tribasic,calcium carbonate DC, a calcium silicate, a combinations of one or moreof the same, or the like. In one aspect of this embodiment, the at leastone filler can be silicified microcrystalline cellulose. The silicifiedmicrocrystalline cellulose can be provided in an amount of about 20% toabout 99.9% w/w; of about 80% to about 99.8% w/w; or of about 94% toabout 98.5% w/w, for example. The compositions can further comprise atleast one of the following second fillers, microcrystalline cellulose,lactose, compressible sugars, xylitol, sorbitol, mannitol,pregelatinized starch, maltodextrin, calcium phosphate dibasic, calciumphosphate tribasic, calcium carbonate DC, a combinations of one or moreof the same, or the like.

In one embodiment, the compositions further can comprise at least oneglidant. In one aspect of this embodiment, the glidant can be, forexample, colloidal silicon dioxide. In one embodiment, the colloidalsilicon dioxide can be provided in an amount of about 0.1 to about 1.5%w/w, for example.

In one embodiment, the compositions further can comprise at least onelubricant. In one embodiment, the lubricant can be, for example,magnesium stearate, calcium stearate, sodium stearyl fumarate, stearicacid, hydrogenated vegetable oil, glyceryl behenate, polyethyleneglycol, a combinations of one or more of the same, and the like. In oneaspect of this embodiment, the lubricant can be magnesium stearate. Inone embodiment, magnesium stearate can be provided, for example, in anamount of about 0.25 to about 1.5% w/w.

In one embodiment, the compositions further can comprise at least onedisintegrant or at least one supplemental binder. In one aspect of thisembodiment, the disintegrant can be, for example, croscarmellose sodium,sodium starch glycolate, crospovidone, microcrystalline cellulose,pregelatinized starch, corn starch, alginic acid, ion exchange resin,combinations of one or more of the same, and the like. In anotherembodiment, the supplemental binder can be, for example, hydroxypropylcellulose, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, or sodium carboxy methylcellulose,combinations of one or more of the same, and the like.

The compositions disclosed herein can be in the form of tablets, filmcoated tablets, capsules, gel caps, caplets, pellets, beads, or thelike. The doxepin can be provided, for example, in an amount of about0.5 mg to about 9 mg. Also, doxepin can be provided in an amount ofabout 1 to about 2 mg. In one embodiment, doxepin can be provided in anamount of about 1 mg. In another embodiment, doxepin can be provided inan amount of about 3 to about 4 mg. In another aspect, doxepin can beprovided in an amount of about 3 mg. In another embodiment, doxepin canbe provided in an amount of about 6 to about 7 mg. In one aspect of thisembodiment, doxepin can be provided in an amount of about 6 mg.

Embodiments of the invention also provide compositions comprising fromabout 0.5 to about 9 mg doxepin having hardness values of at least 2 Kp,for example. In other embodiments, the compositions have hardness valuesof at least 4 Kp, at least 6 Kp, at least 8 Kp, at least 10 Kp or about12 Kp, for example.

There is also provided a tablet, including a film coated tablet,comprising from about 0.5 to about 9 mg doxepin having a friabilityvalue of 1% or less, for example. In other embodiments, the tablet canhave a friability value of about 0.75%, of about 0.5% or of about 0.25%,for example.

Embodiments of the invention also provide pharmaceutical compositionscomprising from about 0.5 to about 9 mg doxepin having disintegrationtimes of less than 1 minute per U.S. Pharmacopeia (USP) protocols(accessible on the world wide web and usp.org; the Pharmacopeia isincorporated herein by reference in its entirety), for example. In otherembodiments, the compositions can have disintegration times of less than30 seconds, of less than 20 seconds, of less than 10 seconds or of lessthan 6 seconds, for example.

Another embodiment provides pharmaceutical compositions comprising fromabout 0.5 to about 9 mg doxepin having at least an 85 percent release ofdoxepin within 30 minutes using U.S. Pharmacopeia (USP) Apparatus I at100 rpm (or Apparatus II at 50 rpm) in 0.1 N HCl or Simulated GastricFluid USP without enzymes. In other embodiments, the composition canhave, for example, at least an 85 percent release rate at 15 minutes, atleast an 85 percent release rate at 10 minutes, at least an 85 percentrelease rate at 5 minutes, at least a 90 percent release rate at 30minutes, at least a 95 percent release rate at 30 minutes. In someaspects of this embodiment, the compositions also can have at least an85 percent release of doxepin within 30 minutes using U.S. Pharmacopeia(USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a pH 4.5buffer and/or at least an 85 percent release of doxepin within 30minutes using U.S. Pharmacopeia (USP) Apparatus I at 100 rpm (orApparatus II at 50 rpm) in a pH 6.8 buffer of Simulated Intestinal FluidUSP without enzymes.

Some embodiments of the invention provide pharmaceutical compositionscomprising from about 0.5 to about 9 mg doxepin having at least an 85percent release of doxepin within 30 minutes using U.S. Pharmacopeia(USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a pH 4.5buffer. In other embodiments, the compositions can have, for example, atleast an 85 percent release rate at 15 minutes, at least an 85 percentrelease rate at 10 minutes, at least an 85 percent release rate at 5minutes, at least a 90 percent release rate at 30 minutes or at least a95 percent release rate at 30 minutes.

Another embodiment provides pharmaceutical compositions comprising fromabout 0.5 to about 9 mg doxepin having at least an 85 percent release ofdoxepin within 30 minutes using U.S. Pharmacopeia (USP) Apparatus I at100 rpm (or Apparatus II at 50 rpm) in a pH 6.8 buffer or SimulatedIntestinal Fluid USP without enzymes.

Embodiments of the invention also provide pharmaceutical compositionscomprising about 0.5 to about 9 mg doxepin having two or more of thefollowing characteristics: a hardness value of at least 2 Kp, afriability value of 1% or less, a disintegration time of less than 1minute as per USP protocols, at least an 85 percent release of doxepinwithin 30 minutes using U.S. Pharmacopeia (USP) Apparatus I at 100 rpm(or Apparatus II at 50 rpm) in 0.1 N HCl or Simulated Gastric Fluid USPwithout enzymes, at least an 85 percent release of doxepin within 30minutes using U.S. Pharmacopeia (USP) Apparatus I at 100 rpm (orApparatus II at 50 rpm) in a pH 4.5 buffer, and at least an 85 percentrelease of doxepin within 30 minutes using U.S. Pharmacopeia (USP)Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a pH 6.8 buffer orSimulated Intestinal Fluid USP without enzymes.

Another embodiment provides a batch of unit dosage forms, eachcomprising from about 0.5 to about 9 mg doxepin, and the batch havingcontent uniformity values between about 85% to 115% of a label claim. Inother embodiments, the batch of unit dosage forms can have, for example,content uniformity values of between about 90% to 110% of label claim orof between about 95% to 105% of label claim. For example, the batch cancomprise at least 50 unit dosage forms, e.g., tablets or film coatedtablets.

In some embodiments the batch of unit dosage forms can comprise fromabout 100,000 to about 10,000,000 units, from about 500,000 to about5,000,000 units, from about 1,000,000 to about 4,000,000 units, or fromabout 3,000,000 to about 4,000,000 units, for example. The units can bein the form of tablets, film coated tablets, capsules, caplets, pills,gel caps, pellets, beads, and the likes

Embodiments of the invention also provide a batch of unit dosage forms,each comprising from about 0.5 to about 9 mg doxepin, having a contentuniformity percent relative standard deviation of less than 5%. In otherembodiments, the batch of unit dosage forms can have, for example, acontent uniformity percent relative standard deviation of less than 4%,less than 3%, less than 2% or less than 1%.

Another embodiment provides a method of treating insomnia, comprisingidentifying an individual in need of such treatment, and administeringany of the compositions disclosed herein to the individual.

Another embodiment relates to a method of treating insomnia, comprisingidentifying an individual in need of such treatment, providing theindividual with instructions to take a doxepin dosage form according toany of the embodiments disclosed herein and providing any of the dosageforms disclosed herein to the individual.

Yet another embodiment provides a method of enhancing sleep maintenance,comprising identifying an individual in need of such enhancement, andadministering any of the compositions disclosed herein to theindividual.

Some embodiments provide methods of making a doxepin dosage formcomprising combining from about 0.5 to about 9 mg doxepin and about 20%to about 99.9% silicified microcrystalline cellulose. In one embodiment,the silicified microcrystalline cellulose can be provided, for example,in amount of about 92% to about 99.8% w/w. The methods can furthercomprise adding from about 0.1 to about 1.5% w/w colloidal silicondioxide and/or about 0.25 to about 1.5% w/w magnesium stearate. In otherembodiments, doxepin can be provided in an amount of about 1 to about 2mg, or about 3 to about 4 mg, or about 7 mg, for example. The silicifiedmicrocrystalline cellulose can be provided in amount of about 92% toabout 99.8% w/w, of about 92% to about 99.8% w/w or of about 92% toabout 99.8% w/w, for example. In another embodiment, doxepin andsilicified microcrystalline cellulose can be combined with at least onefiller selected from microcrystalline cellulose, lactose, compressiblesugars, xylitol, sorbitol, mannitol, pregelatinized starch,maltodextrin, calcium phosphate dibasic, calcium phosphate tribasic,calcium carbonate DC, combinations of one or more of the same, and thelike.

Embodiments of the invention also provide methods of making doxepindosage forms comprising serially diluting and mixing a low concentrationof doxepin with a higher concentration formulation excipient.

There is also provided a method of manufacturing a doxepin dosage form,wherein the method includes forming a drug substance pre-blend by mixingsilicified microcrystalline cellulose and doxepin; forming a final blendby mixing silicified microcrystalline cellulose and the drug substancepre-blend; and forming a doxepin dosage form from the final blend. Inone embodiment, the final blend can be compressed to form a doxepintablet. The doxepin tablet also can be a film coated tablet. In someembodiments, the method can further comprise screening the drugsubstance pre-blend prior to forming the main blend. In anotherembodiment, the method further can comprise mixing the final blend for atime period sufficient to obtain a uniform distribution of doxepin priorto forming the tablet. In yet another embodiment, the method further cancomprise mixing the final blend with magnesium stearate prior to formingthe tablet. In some aspects the methods can include applying a coatingto form a film coated tablet.

Another embodiment is a method of manufacturing a doxepin dosage form,wherein the method includes forming a drug substance pre-blend by mixinga first filler and doxepin; forming a final blend by mixing a secondfiller and the drug substance pre-blend; and forming a doxepin dosageform from the final blend. In one aspect of this embodiment, the firstfiller and the second filler can be, for example, silicifiedmicrocrystalline cellulose, microcrystalline cellulose, lactose,compressible sugars, xylitol, sorbitol, mannitol, pregelatinized starch,maltodextrin, calcium phosphate dibasic, calcium phosphate tribasic,calcium carbonate DC, combinations of one or more of the same, and thelike. In one embodiment, the first and second fillers are not the same.In one embodiment, the first and/or the second filler can be silicifiedmicrocrystalline cellulose. In another embodiment, the first and secondfillers can be the same. In yet another embodiment, the first and thesecond filler can be silicified microcrystalline cellulose. In anotherembodiment, the drug substance pre-blend or the final blend can comprisean additional filler. The additional filler can be, for example,silicified microcrystalline cellulose, microcrystalline cellulose,lactose, compressible sugars, xylitol, sorbitol, mannitol,pregelatinized starch, maltodextrin, calcium phosphate dibasic, calciumphosphate tribasic, calcium carbonate DC, combinations of one or more ofthe same, and the like.

Embodiments of the invention also provide methods of manufacturing adoxepin dosage form by direct compression. The methods can include, forexample, forming a color blend by mixing one or more pharmaceuticallyacceptable colorants and silicified microcrystalline cellulose; formingan initial drug substance pre-blend by mixing silicifiedmicrocrystalline cellulose and doxepin; forming a final drug substancepre-blend by mixing the color blend and initial drug substancepre-blend; screening the final drug-substance pre-blend; forming a mainblend by mixing silicified microcrystalline cellulose and the finaldrug-substance pre-blend; mixing the main blend for a time periodsufficient to obtain a uniform distribution of doxepin; forming a finalblend by mixing a lubricant and the main blend; and forming the finalblend into a doxepin dosage form.

In one aspect of this embodiment, forming the initial drug substancepre-blend can comprise sequentially screening a first portion of thesilicified microcrystalline cellulose, screening the doxepin, andscreening a second portion of the silicified microcrystalline cellulose.In some aspects, the methods preferably can include methods to preventre-agglomeration of the materials. For example, the screened powders canbe placed into a blender and mixed, and the initial drug substancepre-blend can be screened using a vibrating sieve, a cone mill or a comill, which operate in manner that prevents re-agglomeration of cohesivepowders. In another embodiment, forming the final drug substancepre-blend can comprise sequentially adding a first portion of the colorpre-blend or filler, adding the initial drug substance pre-blend, andadding a second portion of the color pre-blend or filler. In anotherembodiment, the final drug substance pre-blend can comprise combiningtwo, equivalent initial drug substance pre-blends.

In another embodiment, color can be imparted with a tablet coatingprocess which obviates the need for a color pre-blend. For the low doseembodiments, in some aspects the absence of a color pre-blend can resultin the preparation of only one drug substance pre-blend rather than aninitial and final drug substance pre-blend. In some embodiments,screening the final drug-substance pre-blend step can be repeated priorto forming the main blend. In another embodiment, screening the finaldrug-substance pre-blend can comprise using a vibrating sieve. Inaspects of this embodiment, the final drug-substance pre-blend can bescreened using a vibrating sieve, for example, equipped with a 10 to 200mesh screen, a 20 to 80 mesh screen, or a 30 mesh screen, or the like.In some embodiments, forming the main blend can comprise sequentiallyadding a first portion of the silicified microcrystalline cellulose,adding the drug-substance pre-blend, and adding a second portion of thesilicified microcrystalline cellulose. In other embodiments, the mainblend can be mixed, for example, for about 5 to about 60 minutes, forabout 10 to about 40 minutes or for about 20 minutes. In one embodiment,the main blend can be mixed, for example, in an in-bin blender. Thelubricant can be, for example, magnesium stearate, calcium stearate,sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil,glyceryl behenate, polyethylene glycol, combinations of one or more ofthe same, and the like. In one embodiment, the lubricant can comprisemagnesium stearate. In some embodiments, the final blend can becompressed to form the tablet, for example.

Another embodiment provides a method of preparing a uniform low-dosedoxepin pre-blend comprising serially diluting and mixing a lowconcentration of doxepin with higher concentration formulationexcipients.

Embodiments of the invention also provide methods of making a pluralityof doxepin dosage forms. The methods can include, for example, providingan amount of doxepin to obtain a plurality of doxepin tablets, includingfilm coated tablets, wherein each tablet comprises between about 0.1 mgto 9 mg of doxepin; providing one or more excipients; mixing saiddoxepin and excipients such that the plurality of doxepin dosage formscomprises at least one of content uniformity values between about 85%and 115% of label claim or a content uniformity percent relativestandard deviation of less than 5%. In other embodiments, the pluralityof dosage forms can comprise content uniformity values between about 90%to 110% of label claim, or between about 95% to 105% of a label claim,for example. In other embodiments, the plurality of dosage forms cancomprise a content uniformity percent relative standard deviation ofless than 5%, of less than 4 of less than 3%, of less than 2%, or ofless than 1%, for example.

In one aspect of this embodiment, the one or more excipients cancomprise SMCC. The one or more excipients can further comprise anexcipient, such as, for example, microcrystalline cellulose, lactose, acompressible sugar, xylitol, sorbitol, mannitol, pregelatinized starch,maltodextrin, calcium phosphate dibasic, calcium phosphate tribasic,calcium carbonate DC, a calcium silicate, and the like. In anotherembodiment, the one or more excipients can comprise, for example,between about 20% and 100% SMCC. In other embodiments, the plurality ofdosage forms can comprise, for example, from about 100,000 to about10,000,000 units, from about 500,000 to about 5,000,000 units, fromabout 1,000,000 to about 4,000,000 units or from about 3,000,000 toabout 4,000,000 units.

Some embodiments relate to pharmaceutical unit dosage form, comprisingdoxepin, a pharmaceutically-acceptable salt or prodrug thereof in anamount equivalent to about 1 mg doxepin hydrochloride; one or morepharmaceutically-acceptable excipients; and optionally, a capsule orcoating. In some embodiments, the excipients and any capsule or coatingcan be selected to provide a swallowable unit dosage that is at leastexternally solid and that has dissolution and bioavailabilitycharacteristics such that after administration to a 70 kg human, thedosage form provides a plasma concentration of at least 0.05 ng/mLdoxepin within a time frame of not more than about 90 minutes, forexample. The dosage form can be a tablet, a film coated tablet, acapsule, a pill, a caplet, a gel cap, a pellet, a bead, or a dragee. Inone embodiment, the dosage form can be a tablet. In some embodiments,the dosage form preferably can be a film coated tablet. In anotherembodiment, the dosage form can be a capsule. In yet another embodiment,the time frame to provide a plasma concentration of at least 0.05 ng/mLis not more than about 80 minutes, for example.

Another embodiment of the invention is directed to a pharmaceutical unitdosage form, comprising doxepin, a pharmaceutically-acceptable salt orprodrug thereof in an amount equivalent to about 1 mg, 3 mg, or 6 mgdoxepin hydrochloride; one or more pharmaceutically-acceptableexcipients; and optionally, a capsule or coating. In some embodiments,the excipients and any capsule or coating can be selected to provide aswallowable unit dosage that is at least externally solid and that hasdissolution and bioavailability characteristics such that afteradministration to a 70 kg human, the dosage form provides a plasmaconcentration of at least 0.1 ng/mL doxepin within a time frame of notmore than about 60 minutes. In yet another embodiment, the time frame toprovide a plasma concentration of at least 0.1 ng/mL is not more thanabout 50 minutes. In some aspects, the dosage form can provide a plasmaconcentration of at least 0.05 ng/mL doxepin within a time frame of notmore than about 90 minutes, for example. The dosage form can be atablet, a film coated tablet, a capsule, a pill, a caplet, a gel cap, apellet, a bead, or a dragee. In one embodiment, the dosage form can be atablet. In some embodiments, the dosage form preferably can be a filmcoated tablet. In another embodiment, the dosage form can be a capsule.

Some embodiments relate to pharmaceutical compositions comprising 0.5 to9 mg doxepin or a pharmaceutically acceptable salt or prodrug of doxepinwhere the composition comprises at least two or more of thecharacteristics of: a hardness value of at least 2 Kp, a friabilityvalue of 1% or less, a disintegration time of less than 1 minute as perU.S. Pharmacopeia (USP) protocols, at least an 80% release of doxepinwithin 15 minutes using compendial method for measuring dissolution ofdoxepin. Preferably, the compositions comprise at least 80% release ofdoxepin within 15 minutes. Also, some embodiments relate to compositionsor formulations that release at least from about 60% to about 99.5%doxepin after about 5 to about 40 minutes. The release or dissolutioncan be determined using the USP-based methods. Preferably, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95% or 99.5% doxepin is released after 3, 5,10, 15 or 30 minutes, for example. Thus, some embodiments relate to lowdose doxepin formulations that have the unexpected dissolutionproperties listed above and elsewhere herein.

Some embodiments relate to methods for processing or producing low dosedoxepin dosage forms, for example, from about 0.5 mg to about 9 mgdoxepin, while obtaining high content uniformity. The methods caninclude minimizing segregation of low dose doxepin, which segregationcan cause a lack of uniformity of dosage forms, by minimizingfluidization of low dose doxepin blended with a filler, including any ofthe fillers listed herein. In some embodiments, the minimizing offluidization can be accomplished by minimizing airflow through a blendof low dose doxepin and one more fillers. Examples of minimizing airflowcan include providing vents, valves or other devices that permit therelease of air from containment devices that transport or hold the lowdose doxepin blend. Also, fluidization can be minimized by reducing theamount of airspace in a dosage form press, such that there is lessopportunity for contact of the blend with air. Also, the low doseformulations can be produced using a wet granulation method in order toavoid fluidization. Furthermore, carriers or fillers that bind withgreater strength to the doxepin can be utilized. Such carriers/fillerscan be easily incorporated by one of skill in the art.

Also, content uniformity can be maintained or enhanced by minimizingagglomeration or re-agglomeration of doxepin in the low dose doxepinformulations. Examples of minimizing agglomeration are described herein.Such methods can include, for example, diluting or layering the low dosedoxepin with one or more fillers (including those listed or describedherein). The methods can also include the use of a cone mill, a co millor the like, including devices that minimize the separation of thedoxepin from filler blends and dilution blends/mixes.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the blend uniformity with and without drugsubstance pre-blend.

FIG. 2 is a graph showing a batch content uniformity comparison.

FIG. 3 is a flow chart showing an exemplary manufacturing process.

FIGS. 4-6 are flow charts showing preparation of a color pre-blend.

FIGS. 7-8 are flow charts showing preparation of a drug substancepre-blend.

FIG. 9 is a flow chart showing preparation of a final blend.

FIG. 10 is a graph showing percentage of tablet dissolved vs. time(min).

FIGS. 11A-B are flow charts showing a fluid bed granulation process foruse in the invention disclosed herein.

FIGS. 12A-B are flow charts showing a wet granulation process for use inthe invention disclosed herein.

FIGS. 13A-B are flow charts showing a dry granulation process for use inthe invention disclosed herein.

FIG. 14 is a manufacturing process flow chart depicting an example of aprocess for film-coated tablets.

FIG. 15 is a graph of the dissolution data for commercially-available,high-dose doxepin formulations as well as lactose and SMCC-basedformulations of low-dose doxepin.

DETAILED DESCRIPTION

Embodiments of the invention generally relate to new and surprisinglyeffective doxepin formulations and methods of using low-dose forms ofdoxepin, including, for example, use in the treatment of insomnia. Also,some embodiments of this invention relate to novel and economicalmethods of manufacturing low-dose dosage forms of doxepin,pharmaceutically acceptable salts thereof, or prodrugs thereof.

Doxepin is a tricyclic compound currently approved for treatment ofdepression or anxiety at a daily dose of 75 mg to 300 mg. Doxepin ismarketed under the commercial name SINEQUAN® and in generic form, andcan be obtained in the United States generally from pharmacies incapsule form in amounts of 10, 25, 50, 75, 100 and 150 mg dosage, and inliquid concentrate form at 10 mg/mL. The capsule formulations containDoxepin HCl with cornstarch and magnesium stearate/sodium laurylsulfate. Capsule shells can also contain gelatin, sodium lauryl sulfate,sodium metabisulfate and colorants. Such capsule formulations orformulations using one or more of the features of the capsuleformulations can be specifically excluded from some embodiments herein.For example, doxepin formulations comprising starch and/or a gelatinshell can be exclude from some embodiments.

The use of low dose doxepin for the treatment of insomnia is describedin U.S. Pat. Nos. 5,502,047 and 6,211,229, the entire contents of whichare incorporated herein by reference. As mentioned above, manyindividuals currently suffer from sleep disorders, such as insomnia.There is a need for improved compositions and methods for treating suchindividuals.

Compounds Doxepin

Doxepin HCl is a tricyclic compound currently approved and available fortreatment of depression and anxiety.

Doxepin belongs to a class of psychotherapeutic agents known asdibenzoxepin tricyclic compounds, and is currently approved andprescribed for use as an antidepressant to treat depression and anxiety.Doxepin has a well-established safety profile, having been prescribedfor over 35 years.

It is contemplated that doxepin for use in the compositions and methodsdescribed herein can be obtained from any suitable source or made by anysuitable method. For example, doxepin HCl can be obtained from PlantexLtd. (DMF No. 3230). In the Biopharmaceutic Classification System,doxepin HCl, USP is designated as a Class One compound, with highsolubility and high permeability. The Plantex-supplied doxepin HCl, USPhas a particle size specification of not less than 80% smaller than 38microns and not less than 90% smaller than 125 microns as measured by anAir Jet Sieve method.

Also, doxepin can be prepared according to the method described in U.S.Pat. No. 3,438,981, which is incorporated herein by reference in itsentirety. As another illustration, doxepin can be prepared from11-[3-(Dimethylamino)propyl]-6,11-dihydrodibenzo[b,e]oxepin-11-ol astaught in U.S. Pat. No. 3,420,851, which is incorporated herein byreference in its entirety. It should be noted and understood thatalthough many of the embodiments described herein specifically refer to“doxepin,” other doxepin-related compounds can also be used, including,for example, pharmaceutically acceptable salts, prodrugs, in-situ saltsof doxepin formed after administration, and solid state forms, includingpolymorphs and hydrates.

Pharmaceutically Acceptable Salts:

As mentioned above, the methods and other embodiments described hereincan utilize any suitable pharmaceutically acceptable salt or prodrug ofdoxepin. Therefore, the substitution or use in combination of salts andprodrugs is specifically contemplated in the embodiments describedherein. The pharmaceutically acceptable salts and prodrugs can be madeby any suitable method.

The term “pharmaceutically acceptable salt” refers to an ionic form of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. Pharmaceutical salts can be obtained byreacting a compound, for example, doxepin, with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. Pharmaceuticalsalts can also be obtained by reacting a compound of the invention witha base to form a salt such as an ammonium salt, an alkali metal salt,such as a sodium or a potassium salt, an alkaline earth metal salt, suchas a calcium or a magnesium salt, a salt of organic bases such asdicyclohexylamine, N-methyl-D-glutamine, tris(hydroxymethyl)methylamine,and salts with amino acids such as arginine, lysine, and the like.Pharmaceutically acceptable salts are more fully described in thefollowing paragraph.

The acids that can be used to prepare pharmaceutically acceptable acidaddition salts include, for example, those that form non-toxic acidaddition salts, i.e., salts containing pharmacologically acceptableanions, such as the acetate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate,carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate,dislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate,gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, subacetate, succinate, tannate,tartrate, teoclate, tosylate, triethiodode, and valerate salts.

The bases that can be used to prepare pharmaceutically acceptable baseaddition salts include, for example, those that form non-toxic baseaddition salts, i.e., base salts formed with metals or amines, such asalkali and alkaline earth metals or organic amines. Non-limitingexamples of metals used as cations include sodium, potassium, magnesium,calcium, and the like. Also included are heavy metal salts such as forexample silver, zinc, cobalt, and cerium. Non-limiting examples ofsuitable amines include N,N′-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamene, N-methylglucamine, andprocaine.

Prodrugs:

The term “prodrug” refers to an agent that is converted into the activedrug in vivo. Prodrugs are often useful because, in some situations,they can be easier to administer than the active drug. They can, forinstance, be bioavailable by oral administration whereas the active drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the active drug. An example, without limitation, of aprodrug would be a compound of the present invention which isadministered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. Examples of prodrug groups can be found in,for example, T. Higuchi and V. Stella, in “Pro-drugs as Novel DeliverySystems,” Vol. 14, A.C.S. Symposium Series, American Chemical Society(1975); H. Bundgaard, “Design of Prodrugs,” Elsevier Science, 1985; and“Bioreversible Carriers in Drug Design: Theory and Application,” editedby E. B. Roche, Pergamon Press: New York, 14-21 (1987), each of which ishereby incorporated by reference in its entirety.

Compositions

Dosage form development requires the selection of excipients based onthe properties of the drug substance being formulated. Several preferredembodiments of this invention are provided. These should not beconstrued as limiting the scope of this invention.

Some embodiments of the invention are based upon the new discovery ofpreviously unknown physical characteristics and challenges associatedwith low-dose doxepin compositions, and also upon a new understanding ofpharmacokinetics of doxepin when it is used to treat sleep disorders.

For example, it has been found that formulation of compositions at thelower dose range can present a considerable challenge in maintainingconsistent potency and uniformity in the drug product manufacturingprocess, while also maintaining a high yield. For example, assuring thehomogeneity of the powder blend for production of low-dose dosage formscan represent a major quality assurance consideration. The selection ofthe particular excipient or excipients used, and how to properly blendand prevent non-uniformity and segregation were based upon previouslyunrecognized characteristics and needs for doxepin formulation,particularly low-dose formulations.

Also, in some embodiments, the compositions are based upon previouslyunknown pharmacokinetics of low-dose doxepin for sleep. Although doxepindissolves quickly in the stomach, it can take some time for the sleeppromoting action of the drug to take place. No one previously recognizedthe sleep pharmacokinetics of doxepin, such as, sleep onsetcharacteristics of doxepin; and for sleep, even decreasing inductiontime by a few minutes can provide an enormous benefit. In the context ofsleep, early onset of drug action can be important due to the discreetwindow of time (e.g., 8 hours) in which a patient needs to sleep. As aconsequence, some embodiments relate to compositions that can contributeto accelerated action of the drug. That need was not recognizedpreviously, in particular for depression and anxiety where there was noneed for fast onset due to the ongoing and chronic nature of thoseconditions. The unique needs of doxepin for treating sleep were notappreciated in the prior art.

Accordingly, some embodiments relate to compositions for the treatmentof such disorders where careful selection of excipients was used toaddress the previously unrecognized characteristics of low-dose doxepinand doxepin for use in treating sleep disorders. Described below andelsewhere herein are new and unexpectedly effective doxepinformulations.

Doxepin HCl, USP, is a white crystalline powder with a slight amine-likeodor supplied by Plantex Ltd. In the Biopharmaceutic ClassificationSystem, doxepin HCl, USP is designated as a Class One compound, withhigh solubility and high permeability (Wu-Benet, 2005). ThePlantex-supplied doxepin HCl, USP has a particle size specification ofnot less than 80% smaller than 38 microns and not less than 90% smallerthan 125 microns as measured by an Air Jet Sieve method.

In a preferred embodiment, the compositions disclosed herein can includefrom about 0.01 mg to about 9 mg of doxepin, or from about 0.5 mg toabout 7 mg doxepin, or from about 1 mg to about 6 mg doxepin. In someembodiments, the compositions include from about 0.5 mg to about 2 mgdoxepin, or from about 2.5 mg to about 4 mg, or from about 5.9 mg toabout 7 mg doxepin.

As discussed above, in some embodiments, doxepin prodrugs orpharmaceutically acceptable salts of doxepin can be used in place of, orin addition to, low-dose doxepin in the formulations described herein.

Some embodiments provide low-dose doxepin tablets, film coated tablets,capsules, caplets, pills, gel caps, pellets, beads, or dragee dosageforms. Some embodiments specifically exclude one or more such dosageforms.

Preferably, the formulations disclosed herein can provide favorable drugprocessing qualities, including, for example, but not limited to, rapidtablet press speeds, reduced compression force, reduced ejection forces,blend uniformity, content uniformity, uniform dispersal of color,accelerated disintegration time, rapid dissolution, low friability(preferable for downstream processing such as packaging, shipping,pick-and-pack, etc.) and dosage form physical characteristics (e.g.,weight, hardness, thickness, friability) with little variation. Many ofthese qualities, notably, content uniformity and blend uniformity, aredifficult to obtain in low dose formulations.

Making the drug available for absorption with minimal delay can beimportant in the treatment of medical conditions such as insomnia. In apreferred embodiment, the formulations can yield extremely rapiddisintegration times of 1 minute or less as per USP protocols.Preferably, the formulation yields disintegration times of 50, 40, 30,25, 10 seconds or less. More preferably, the formulation yields dosageform disintegration times of 8 seconds or less, and even more preferably6 seconds or less. In a preferred embodiment, silicifiedmicrocrystalline cellulose (SMCC), e.g., Prosolv SMCC® (JRS Pharma Inc.,Patterson, N.Y.) is used as a diluent or filler to impart favorabledisintegration times.

In other embodiments, the formulation yields a rapidly dissolving dosageform, for which at least 85% of the labeled amount of the drug substancedissolves within 30 minutes, using U.S. Pharmacopeia (USP) Apparatus Iat 100 rpm (or Apparatus II at 50 rpm) in a volume of 900 ml or less ineach of the following media: (1) 0.1 N HCl or Simulated Gastric FluidUSP without enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer orSimulated Intestinal Fluid USP without enzymes.

In some embodiments, the formulations require minimal tablet compressionforces to achieve a hardness of about 2 to about 25 kp. In some aspects,the formulation can require compression forces to achieve a hardness of,for example, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 20 or21 kp. Such minimal compression forces can enables the tablets to remainrelatively porous and disintegrate fast with minimal wear on compressiontooling and the tablet press. In one embodiment of the inventiondisclosed herein, the use of SMCC as a diluent imparts favorablecompressibility and disintegration of the dosage form.

In other embodiments, the formulations can yield tablets, including filmcoated tablets, having a friability value of 1% or less. Thus, in someembodiments, the friability value is about 0.9%, 0.8%, 0/75%, 0.6%,0.5%, 0.4%, 0.3%, 0.25% or less.

Preferably, the formulations disclosed herein provide a batch oflow-dose doxepin dosage forms having content uniformity values betweenabout 75% to about 125% of label claim, or from about 85% to about 115%of label claim, more preferably between about 90% to about 110% of labelclaim, and more preferably between about 95% to about 105% of labelclaim. In some embodiments, the formulations yield a batch of low-dosedoxepin dosage forms having a content uniformity percent relativestandard deviation of 7.8% or less. In some embodiments, the relativestandard deviation is equal to or less than 6%, 5%, 4%, 3%, 2%, or 1%.Preferably, the formulations disclosed herein provide a high yield oflow-dose doxepin dosage forms having acceptable content uniformity. Thebatch can include, for example, about from about 50 to about 5,000,000unit dosage forms or any amount in between, or even more if desired.

In other preferred embodiments, tablet ejection forces are very lowenabling lubrication levels to be kept low and preventing adverseeffects due to over lubrication, including, for example, soft tablets,retarded dissolution, etc. This further reduces wear on compressiontooling. In a preferred embodiment, the use of SMCC permits the use oflow ejection forces.

In some embodiments, the product does not exhibit a sensitivity ofproduct performance (tablet hardness and dissolution) to the lubricantblend time. For example, in one embodiment the SMCC based formulationunexpectedly and surprisingly is resistant to the impact ofover-lubrication normally associated with magnesium stearate. In manycases, lubricant blend time can affect product performance. Verysurprisingly, here lubrication with magnesium stearate can result in lowdose doxepin formulations that are resistant to the normalover-lubrication effects.

In a preferred embodiment, the low-dose dosage forms described hereinare formulated to yield two or more favorable drug characteristics.

The compounds can be formulated readily, for example, by combining thedrug substance with any suitable pharmaceutically acceptable excipientfor example, but not limited to, binders, diluents, disintegrants,lubricants, fillers, carriers, and the like, as set forth below. Suchcompositions can be prepared for storage and for subsequent processing.

Acceptable excipients for therapeutic use are well known in thepharmaceutical art, and are described, for example, in Handbook ofPharmaceutical Excipients, 5th edition (Raymond C Rowe, Paul J Sheskeyand Siân C Owen, eds. 2005), and Remington: The Science and Practice ofPharmacy, 21st edition (Lippincott Williams & Wilkins, 2005), each ofwhich is hereby incorporated in its entirety. The term “carrier”material or “excipient” herein can mean any substance, not itself atherapeutic agent, used as a carrier and/or diluent and/or adjuvant, orvehicle for delivery of a therapeutic agent to a subject or added to apharmaceutical composition to improve its handling or storage propertiesor to permit or facilitate formation of a dose unit of the compositioninto a discrete article such as a capsule, tablet, film coated tablet,caplet, gel cap, pill, pellet, bead, and the like suitable for oraladministration. Excipients can include, by way of illustration and notlimitation, diluents, disintegrants, binding agents, wetting agents,polymers, lubricants, glidants, substances added to mask or counteract adisagreeable taste or odor, flavors, colorants, fragrances, andsubstances added to improve appearance of the composition.

Acceptable excipients include, for example, but are not limited to,SMCC, microcrystalline cellulose, lactose, sucrose, starch powder, maizestarch or derivatives thereof, cellulose esters of alkanoic acids,cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinyl-pyrrolidone,and/or polyvinyl alcohol, saline, dextrose, mannitol, lactose, lecithin,albumin, sodium glutamate, cysteine hydrochloride, and the like.Examples of suitable excipients for soft gelatin capsules includevegetable oils, waxes, fats, semisolid and liquid polyols. Suitableexcipients for the preparation of solutions and syrups include, withoutlimitation, water, polyols, sucrose, invert sugar and glucose. Thecompound can also be made in microencapsulated form. If desired,absorption enhancing preparations (for example, liposomes), can beutilized.

The compositions and formulations can include any other agents thatprovide improved transfer, delivery, tolerance, and the like. Thesecompositions and formulations can include, for example, powders, pastes,jellies, waxes, oils, lipids, lipid (cationic or anionic) containingvesicles (such as Lipofectin™), DNA conjugates, anhydrous absorptionpastes, oil-in-water and water-in-oil emulsions, emulsions carbowax(polyethylene glycols of various molecular weights), semi-solid gels,and semi-solid mixtures containing carbowax.

Any of the foregoing mixtures can be appropriate in treatments andtherapies in accordance with the invention disclosed herein, providedthat the active ingredient in the formulation is not inactivated by theformulation and the formulation is physiologically compatible andtolerable with the route of administration. See also Baldrick P.“Pharmaceutical excipient development: the need for preclinicalguidance.” Regul. Toxicol. Pharmacol. 32(2):210-8 (2000), Charman W N“Lipids, lipophilic drugs, and oral drug delivery-some emergingconcepts.” J Pharm Sci 0.89(8):967-78 (2000), and the citations thereinfor additional information related to formulations, excipients andcarriers well known to pharmaceutical chemists.

In some embodiments, one or more, or any combination of the listedexcipients can be specifically included or excluded from theformulations and/or methods disclosed herein. For example, in someembodiments, microcrystalline cellulose can be specifically excluded.

The formulation can be in form suitable for bolus administration, forexample. Oral administration can be accomplished using orallyadministered formulations, for example, tablets, film coated tablets,capsules, gel caps, caplets, pellets, beads, pills, and the like. Inaddition, stabilizers can be added. All formulations for oraladministration should be in dosages suitable for such administration.

As will be appreciated by those of skill in the art, the amounts ofexcipients will be determined by drug dosage and dosage form size. Insome embodiments disclosed herein, the dosage form size is 150 mg. Thisdosage form weight is arbitrary and one skilled in the art will realizethat a range of weights can be made and are encompassed by thisinvention. The preferred dosage form range is 50 mg to 500 mg, morepreferably 75 mg to 300 mg, more preferably 100 to 200 mg, with thepreferred dosage form weight being 150 mg.

In some embodiments, a high functionality excipient can be used in theformulations. The term “high functionality excipient” is defined as aninactive ingredient that meets the following four criteria: (1)multifunctional in that one excipient contributes two or more functionsto a formulation, (2) high inherent functional performance even at lowuse levels, allowing for increased batch sizes and higher drug loading(3) does not require complex processing steps, making it ideal for costeffective direct compression processes and (4) imparts high inherentfunctional performance to the overall formulation. High functionalityexcipients provide the means for simplifying formulation development,and improving overall operational costs while preserving the qualitythat is essential for pharmaceutical products.

In a preferred embodiment, low doses of doxepin are combined withsilicified microcrystalline cellulose (SMCC), e.g., Prosolv SMCC® (JRSPharma Inc., Patterson, N.Y.). For example, based on a 150 mg dosageform weight, the range of drug substance is from about 0.75% to about4.5% w/w and the range of SMCC is from about 90 to 99.8% w/w, or fromabout 92% to about 99% w/w, or from about 94% to about 98.5% w/w.

“Silicified microcrystalline cellulose,” also referred to by the acronym“SMCC”, is composed of 98% microcrystalline cellulose USP/NF and 2%colloidal silicon dioxide USP/NF. The silicification of themicrocrystalline cellulose forms an intimate association between thecolloidal silicon dioxide and the microcrystalline cellulose. SMCCprovides the role of a high functionality excipient and imparts thefunctions of diluent, binder and/or disintegrant. The use of SMCC isdisclosed in U.S. Pat. Nos. 5,585,115, 5,725,884, 5,866,166, 6,217,909,6,358,533, 6,471,994, 6,521,261, 6,476,693, 6,936,277, each of which ishereby incorporated by reference in its entirety. Several grades of SMCCare currently available, with particle size and bulk density being aprinciple differentiating properties among the grades. Preferably, theparticle size of the diluent can be selected based on consideration ofthe particle size of the drug substance. In one embodiment of theinvention disclosed herein, the particular grade has a median particlesize (by sieve analysis) of approximately 90 μm.

The silicified microcrystalline cellulose used in the preparationsdisclosed herein can be any combination of microcrystalline celluloseco-processed with colloidal silicon dioxide, including, for example,that which can be obtained commercially from JRS Pharma Inc. under thename ProSolv SMCC®. There are different grades of SMCC available, withparticle size and bulk density being exemplary differentiatingproperties among the grades. It should be noted that as described below,other excipients can be used in combination with or substituted for SMCCin order to formulate suitable doxepin dosage forms.

The use of SMCC as a diluent or filler imparts favorable drug processingqualities, including, for example, but not limited to, rapid tabletpress speeds, reduced compression force, reduced ejection force, blenduniformity, content uniformity, uniform dispersal of color, accelerateddisintegration time, rapid dissolution, low friability (preferable fordownstream processing such as packaging, shipping, pick-and-pack, etc.)and dosage form physical characteristics (e.g., weight, hardness,thickness, friability) with little variation.

In addition, SMCC is easily compacted (an efficient binder) andpossesses effective disintegration properties. These two characteristicscreate hard tablets that rapidly dissolve. In some embodiments, SMCC isalso used to serially dilute the drug substance and colorants to promotetheir uniform distribution in the formulation as well as to dry-rinsethe equipment surfaces to minimize any potential loss of drug substanceduring the manufacturing process.

In one embodiment, a dry pharmaceutical blend of silicifiedmicrocrystalline cellulose and low-dose doxepin, or a low-dosedoxepin-related compound, is used to produce the final dosage form bydirect compression. Typically, the dry blend contains from about 0.1% toabout 10% w/w, or from about 0.5% to about 5% w/w, or from about 0.7% toabout 4.5% w/w of low-dose doxepin or a low-dose doxepin-relatedcompound. In one embodiment, the doxepin or doxepin-related compound, inthe dry blend is non-granulated. In addition to doxepin, the blend cancontain from about 20% to about 99.9% w/w SMCC, or from about 50% toabout 99.5% w/w SMCC, or from about 75% to about 99% w/w SMCC, or fromabout 80% to about 98.7% SMCC, or from about 92% to about 98.5% w/wSMCC, or from about 94% to about 98% w/w SMCC.

In some embodiments, SMCC can be combined or replaced with one or moreof the following excipients: microcrystalline cellulose, lactosemonohydrate (spray dried), a compressible sugar, xylitol (Xylitab),sorbitol, mannitol, pregelatinized starch, maltodextrin, calciumphosphate dibasic, calcium phosphate tribasic, calcium carbonate DC, andthe like. Accordingly, in one embodiment, one or more of the aboveexcipients can be combined with SMCC in various ratios. For example,assuming the total filler to be 100%, about 80% SMCC can be combinedwith about 20% of one or more alternate filler(s). Alternatively, about70% SMCC can be combined with about 30% of one or more alternatefiller(s), or about 60% SMCC can be combined with about 40% of one ormore alternate filler(s), or about 50% SMCC can be combined with about50% of one or more alternate filler(s), or about 40% SMCC can becombined with about 60% of one or more alternate filler(s), or about 30%SMCC can be combined with about 70% of one or more alternate filler(s),or about 20% SMCC can be combined with about 80% of one or morealternate filler(s).

In alternate embodiments, SMCC can be replaced with one or morealternate excipients. Preferably, alternate excipients are selected toprovide favorable drug processing qualities. For example, in oneembodiment a 50:50 ratio of microcrystalline cellulose to lactose can beused in place of SMCC. In this example, the overall compressibility ofthe lactose would be improved allowing for less compression forceresulting in a more porous tablet, film coated tablet, caplet, pellet,bead, or pill that can show improved dissolution over themicrocrystalline cellulose or lactose alone. Other favorable excipientcombinations will be apparent to one of skill in the art.

The dry blend can also include at least one additional suitablepharmaceutically acceptable excipient. Additional excipients can includeprocessing aids that improve the direct compression tablet-formingproperties of the dry blend, and/or powder flowability. In the dryblend, excipients suitable for use in direct compression include, butare not limited to, binders, diluents, disintegrants, lubricants,fillers, carriers, and the like as set forth above.

In one embodiment, the formulation comprises a mixture of the drugsubstance with SMCC, and additional processing aides, such as, forexample, magnesium stearate and colloidal silicon dioxide, andoptionally, colorant(s). For example, in some embodiments, colloidalsilicon dioxide, which is a component of SMCC, is also added separatelyto the formulation as a glidant to facilitate mass flow of the powdermixture during blending and tablet compression operations. Colloidalsilicon dioxide can be added at concentrations ranging from about 0.1%to about 5.0% w/w, or from about 0.25% to about 2% w/w, or from about0.5% to about 1% w/w.

In some embodiments, magnesium stearate can be added as a lubricant, forexample, to improve powder flow, prevent the blend from adhering totableting equipment and punch surfaces and provide lubrication to allowtablets to be cleanly ejected from tablet dies. Magnesium stearate cantypically be added to pharmaceutical formulations at concentrationsranging from about 0.1% to about 5.0% w/w, or from about 0.25% to about2% w/w, or from about 0.5% to about 1% w/w.

In some embodiments, color additives also can be included. The colorantscan be used in amounts sufficient to distinguish dosage form strengths.Preferably, color additives approved for use in drugs (21 CFR 74, whichis incorporated herein by reference in its entirety) are added to thecommercial formulations to differentiate tablet strengths. The use ofother pharmaceutically acceptable colorants and combinations thereof areencompassed by the current invention.

Binders can be used, for example, to impart cohesive qualities to aformulation, and thus ensure that the resulting dosage form remainsintact after compaction. Suitable binder materials include, but are notlimited to, microcrystalline cellulose, gelatin, sugars (including, forexample, sucrose, glucose, dextrose and maltodextrin), polyethyleneglycol, waxes, natural and synthetic gums, polyvinylpyrrolidone,cellulosic polymers (including, for example, hydroxypropyl cellulose,hydroxypropyl methylcellulose, methyl cellulose, hydroxyethyl cellulose,and the like).

Accordingly, in some embodiments, the formulations disclosed herein caninclude at least one binder to enhance the compressibility of the majorexcipient(s). For example, the formulation can include at least one ofthe following binders in the following preferred ranges: from about 2 toabout 6% w/w hydroxypropyl cellulose (Klucel), from about 2 to about 5%w/w polyvinylpyrrolidone (PVP), from about 1 to about 5% w/wmethycellulose, from about 2 to about 5% hydroxypropyl methycellulose,from about 1 to about 5% w/w ethylcellulose, from about 1 to about 5%w/w sodium carboxy methylcellulose, and the like. The above ranges areexemplary preferred ranges. One of ordinary skill in the art wouldrecognize additional binders and/or amounts that can be used in theformulations described herein. As would be recognized by one of ordinaryskill in the art, when incorporated into the formulations disclosedherein, the amounts of the major filler(s) and/or other excipients canbe reduced accordingly to accommodate the amount of binder added inorder to keep the overall unit weight of the tablet unchanged. In oneembodiment, the binder(s) is(are) sprayed on from solution, e.g. wetgranulation, to increase binding activity.

Lubricants can be employed herein in the manufacture of certain dosageforms. For example, a lubricant will often be employed when producingtablets. In an embodiment of the invention disclosed, a lubricant can beadded just before the tableting step, and can be mixed with theformulation for a minimum period of time to obtain good dispersal. Insome embodiments, one or more lubricants can be used. Examples ofsuitable lubricants include, but are not limited to, magnesium stearate,calcium stearate, zinc stearate, stearic acid, talc, glyceryl behenate,polyethylene glycol, polyethylene oxide polymers (for example, availableunder the registered trademarks of Carbowax® for polyethylene glycol andPolyox® for polyethylene oxide from Dow Chemical Company, Midland,Mich.), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate,sodium stearyl fumarate, DL-leucine, colloidal silica, and others asknown in the art. Preferred lubricants are magnesium stearate, calciumstearate, zinc stearate and mixtures of magnesium stearate with sodiumlauryl sulfate. Lubricants can comprise from about 0.25% to about 10% ofthe tablet weight, more preferably from about 0.5% to about 3%.

Thus, in some embodiments, the formulations disclosed herein can includeat least one lubricant in the following preferred ranges: from about0.25 to about 2% w/w magnesium stearate, from about 0.25 to about 2% w/wcalcium stearate, from about 0.25 to about 2% w/w sodium stearylfumarate, from about 0.25 to about 2% w/w stearic acid, from about 0.25to about 2% w/w hydrogenated vegetable oil, from about 0.25 to about 2%w/w glyceryl behenate, from about 0.25 to about 2% w/w polyethyleneglycol 4000-6000, and the like. The above ranges are examples ofpreferred ranges. One of ordinary skill in the art would recognizeadditional lubricants and/or amounts that can be used in theformulations described herein. As would be recognized by one of ordinaryskill in the art, when incorporated into the formulations disclosedherein, the amounts of the major filler(s) and/or other excipients canbe reduced accordingly to accommodate the amount of lubricant(s) addedin order to keep the overall unit weight of the tablet unchanged.

Disintegrants can be used, for example, to facilitate tabletdisintegration after administration, and are generally starches, clays,celluloses, algins, gums or crosslinked polymers. Suitable disintegrantsinclude, but are not limited to, crosslinked polyvinylpyrrolidone(PVP-XL), sodium starch glycolate, and croscarmellose sodium. Ifdesired, the pharmaceutical formulation can also contain minor amountsof nontoxic auxiliary substances such as wetting or emulsifying agents,pH buffering agents and the like, for example, sodium acetate, sorbitanmonolaurate, triethanolamine sodium acetate, triethanolamine oleate,sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polyoxyethylenesorbitan fatty acid esters, etc. and the like.

In some embodiments, at least one additional disintegrant can beincluded in the following preferred ranges: from about 1 to about 3% w/wcroscarmellose sodium, from about 4 to about 6% w/w sodium starchglycolate, from about 2 to about 4% w/w crospovidone, from about 10 toabout 20% w/w microcrystalline cellulose, from about 5 to about 10% w/wpregelatinized starch, from about 5 to about 10% w/w corn starch, fromabout 5 to about 10% w/w alginic acid, from about 1 to about 5% w/w ionexchange resin (Amberlite 88), and the like. The above ranges areexamples of preferred ranges. One of ordinary skill in the art wouldrecognize additional disintegrants and/or amounts of disintegrants thatcan be used in the formulations described herein. As would be recognizedby one of ordinary skill in the art, when incorporated into theformulations disclosed herein, the amounts of the major filler(s) and/orother excipients can be reduced accordingly to accommodate the amount ofdisintegrant added in order to keep the overall unit weight of thetablet unchanged.

In some embodiments, the formulations can include a coating, forexample, a film coating. Where film coatings are involved, coatingpreparations can include, for example, a film-forming polymer, aplasticizer, or the like. Also, the coatings can include pigments and/oropacifiers. Non-limiting examples of film-forming polymers includehydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose,polyvinyl pyrrolidine, and starches. Non-limiting examples ofplasticizers include polyethylene glycol, tributyl citrate, dibutylsebecate, castor oil, and acetylated monoglyceride. Furthermore,non-limiting examples of pigments and opacifiers include iron oxides ofvarious colors, lake dyes of many colors, titanium dioxide, and thelike.

Dosage

The selected dosage level can depend upon, for example, the route ofadministration, the severity of the condition being treated, and thecondition and prior medical history of the patient being treated.However, it is within the skill of the art to start doses of thecompound at levels lower than required to achieve the desiredtherapeutic effect and to gradually increase the dosage until thedesired effect is achieved with an acceptable safety profile. It will beunderstood, however, that the specific dose level for any particularpatient can depend upon a variety of factors including, for example, thegenetic makeup, body weight, general health, diet, time and route ofadministration, combination with other drugs and the particularcondition being treated, and its severity. For the treatment ofinsomnia, preferably one dose is administered prior to bedtime.

As used herein, the term “unit dosage form,” refers to physicallydiscrete units suitable as unitary dosages for human and animalsubjects, each unit containing a predetermined quantity of doxepincalculated in an amount sufficient to produce the desired effect inassociation with a pharmaceutically acceptable excipient, carrier orvehicle. In some embodiments, the unit dosage form can be, for example,a pill, a tablet, a film coated tablet, capsule, a caplet, a gel cap, apellet, a bead, or the like. In some embodiments, the unit dosage formcan be a tablet. In some embodiments, the unit dosage form can be a filmcoated tablet. In some embodiments, the amount of doxepin in a unitdosage form can be about 0.5 mg to about 9 mg, or about 1 mg to about 9mg, or about 1 mg to about 6 mg.

In some embodiments, daily dosages of low dose doxepin can be about 1,2, 3, 4, 5, 6, 7, 8, or 9 milligrams. In one embodiment, an initialdaily dosage of about 1 milligram can be given. If the desiredimprovement in sleep is not achieved, then the dosage can beincrementally increased until the desired effect is achieved or until amaximum desired dosage is reached which can be, for example, 2milligrams, 3 milligrams, 4 milligrams, 5 milligrams or 6 milligrams. Itshould be noted that other dosages of doxepin can be used in theembodiments described herein. For example, the dosage can be about 0.1to about 10 milligrams.

The term “low dose” can refer to a daily dose range of between about0.01 and 9 milligrams, or to even lower doses. In some embodiments thepreferable dosage of doxepin can be between about 0.1 milligram and 9milligrams. Preferably, the dosage can be about 0.1 milligrams, about0.2 milligrams, about 0.3 milligrams, about 0.5 milligrams, about 1milligram, about 2 milligrams, about 3 milligrams, about 4 milligrams,about 5 milligrams, 6 milligrams, about 7 milligrams, about 8milligrams, or about 9 milligrams.

It should be noted that in some embodiments the formulations and methodsdescribed herein can be applied to any dosage of doxepin, includinghigher doses used to treat depression and anxiety. As one example, theformulations and methods can be applied to dosages between about 10milligrams and 20 milligrams or higher.

Methods of Making Compositions

The compositions described herein can be made by any suitable process,including any process that results in the a composition having one ormore of the properties described herein. Several examples of processesand methods that can be used to make compositions are described herein.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipients with a pharmaceutical composition as describedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. In one embodiment, the compositions canbe prepared using a dry granulation process. Alternatively, a wetgranulation process can be used. In other embodiments, fluid bedgranulation processing techniques are used.

One such granulation method is the “wet” granulation process, whereindry solids (drug substance, filler, binder etc.) are blended andmoistened with water or another wetting agent (e.g. an alcohol) andagglomerates or granules are built up of the moistened solids. Wetmassing is continued until a desired homogenous particle size has beenachieved whereupon the granulated product is dried. Some embodiments caninclude the use of wet granulation processes as part of the methods ofmaking compositions.

In a preferred embodiment, the compositions disclosed herein can beprepared using direct compression. In another preferred embodiment,compressed tablets can be film coated. In some embodiments of theinvention disclosed herein, the use of wet granulation techniques can bespecifically excluded.

As used herein, “direct compression” means that the solid unit dosageform is prepared by compression of a simple mixture of the activepharmaceutical ingredient and excipients, without the active ingredienthaving been subjected to an intermediate granulation process in order toembed it in a larger particle and improve its fluidity properties.

In direct compression, the formulation ingredients, including the activepharmaceutical ingredient and processing aids, are incorporated into afree flowing blend. In one embodiment, the active ingredient,excipients, and other substances are blended and then compressed intotablets. Tablets are typically formed by pressure being applied to amaterial in a tablet press. Compressed tablets can be film coated.

Advantages of direct compression over wet and dry granulation processes,can include, for example, shorter processing times and cost advantages.

In one embodiment, a dry blend is used in forming low-dose doxepin ordoxepin-related compound tablets, including film coated tablets, throughgravity-fed, direct compression tableting. By “gravity fed tabletingpress” it is meant that a pharmaceutical formulation is not force fedinto a die, and that the flow of the pharmaceutical formulation isinduced by gravity. An example of a gravity fed tableting press is theManesty F-press.

Preferably, the doxepin hydrochloride tablet products (including filmcoated and non-film coated tablets) disclosed herein are manufacturedwith common and simple processes including direct blending, compressionand film-coating using commercially available pharmaceutical equipment.These operations utilize readily available equipment, do not expose theAPI to excessive moisture and heat, and are scalable. Preferably, thecommercial manufacturing process produces and maintains blends andtablets with uniform potency that meet all quality characteristics. In apreferred embodiment, the manufacturing processes for all dosagestrength formulations can be the same.

The manufacturing process can include the steps of: (1) preparing acolor pre-blend; (2) preparing a drug substance pre-blend (also known asan active blend); (3) creating a main blend with all ingredients exceptmagnesium stearate (lubricant); (4) adding lubricant and performing thefinal blend mixing step; (5) compressing the blend to produce tabletsand (6) film-coating tablets. In some aspects, one or more of theabove-listed steps can be excluded and the steps can be performed in anysuitable order, not just the listed order.

The process can optionally include several techniques to facilitateformation of blends and batches of finished drug product withhomogeneous distribution of drug substance and colorants including, forexample: (1) de-agglomerating ingredients prior to blending; and/or (2)layering the drug substance and colorant components between additions ofSMCC prior to mixing to create uniform pre-blends; and/or (3) seriallydiluting the drug substance and colorant pre-blends with SMCC and otherformulation excipients to create uniform final blends. In addition, theprocess can optionally include, for example, (1) performing blend mixingtime studies and assessing drug substance uniformity; and/or (2)optimizing the blend batch size with respect to the effective workingcapacity of the blenders.

Efficient mixing and acceptable blend and content uniformity aredifficult to obtain for low dose dosage forms. Preferably, the choice ofblenders and the configuration of the storage container to tablet presspowder transfer chute are selected based on optimization and maintenanceof content uniformity. In addition, excipients and process parameterscan be selected to optimize main compression force and tablet pressspeed on the physical characteristics (hardness, friability, thicknessand weight) of the finished dosage form.

In addition, the process can be optimized to compensate for the tendencyfor fluidization segregation of drug substance. For example,fluidization segregation can be reduced by eliminating process stepsduring which streams of air come in contact with the powder, forexample, the step in the process when the blend is discharged from aV-blender into storage containers, and/or the step in the process whenpowder is fed from storage containers to the tablet press feed hopper.

In a preferred embodiment, the formulation is simple and contains fewfunctional components. Thus, in one embodiment, SMCC can be the majorexcipient and no additional diluents, binders or disintegrants are usedto achieve a readily compressible tablet formulation. In anotherembodiment, only one or two additional excipients are used.

Preferably, the formulation can have excellent compression and flowproperties and the tablet press can be operated at very high pressspeeds and this allows relatively manageable tablet press run times foreven large batch sizes.

In some embodiments, the direct compression manufacturing processesdisclosed herein achieve a uniform drug product of a small unit dose ofdrug substance without the need for complex wet or dry granulationmanufacturing techniques. In a preferred embodiment, the manufacturingprocess avoids costly techniques, such as those requiring large capitalequipment investments, long manufacturing cycle times and associated lowthroughput.

In one embodiment, the manufacturing process is designed to achieve auniform blend by using multiple blending steps, a specific order ofaddition in the blenders and screening steps to facilitate effectivedispersion of the drug substance and excipients. For example, ascreening step can be introduced to prevent agglomerates of drugsubstance from being carried over to subsequent manufacturing steps.

In another embodiment, the manufacturing process is designed to maintainthe uniform blend through to tableting via minimizing the transfersteps, for example, by using an in-bin blender to form the final blendand for example via use of a vented and valved transfer chute to thetablet press.

Methods of Using Low Dose Doxepin

Some embodiments relate to methods for improving sleep in a patient inneed thereof, for example by providing or administering low-dosedoxepin, or a low-dose doxepin-related compound, in a tablet formulation(including coated tablet formulations) as described herein. The term“administer” and its variants contemplate both self-administration (bythe patient) and administration by a third party. In a preferredembodiment, the oral pharmaceutical SMCC-containing doxepin formulationsdescribed herein are administered orally.

As mentioned above and elsewhere, the methods described herein can beused to treat individuals suffering from a sleep disorder, such asinsomnia. The individual can suffer from a chronic insomnia or anon-chronic insomnia. For chronic (e.g., greater than 3-4 weeks) ornon-chronic insomnias, a patient may suffer from difficulties in sleeponset, sleep maintenance (interruption of sleep during the night byperiods of wakefulness), sleep duration, sleep efficiency, prematureearly-morning awakening, or a combination thereof. Also, the insomniamay be attributable to the concurrent use of other medication, forexample. The non-chronic insomnia can be, for example, a short terminsomnia or a transient insomnia. The chronic or non-chronic insomniacan be a primary insomnia or an insomnia that is secondary orattributable to another condition, for example a disease such asdepression or chronic fatigue syndrome. In some aspects, the patient canbe one that is not suffering from an insomnia that is a component of adisease, or a patient can be treated that is otherwise healthy. Aspreviously mentioned, the chronic or non-chronic insomnia can be aprimary insomnia, that is, one that is not attributable to anothermental disorder, a general medical condition, or a substance. In manycases, such conditions may be associated with a chronic insomnia and caninclude, but are not limited to, insomnia attributable to a diagnosableDSM-IV disorder, a disorder such as anxiety or depression, or adisturbance of the physiological sleep-wake system. In some aspects theinsomnia can be non-chronic, or of short duration (e.g., less than 3-4weeks). Examples of causes of such insomnia may be extrinsic orintrinsic and include, but are not limited to environmental sleepdisorders as defined by the International Classification of SleepDisorders (ICSD) such as inadequate sleep hygiene, altitude insomnia oradjustment sleep disorder (e.g., bereavement). Also, short-term insomniamay also be caused by disturbances such as shift-work sleep disorder.

It should be noted that in some aspects, the methods can specificallyexclude one or more of any of the sleep disorders described in theprevious paragraph or elsewhere herein. For example, without beinglimited thereto, in some aspects the methods can specifically excludetreating a chronic insomnia. As another example, without being limitedthereto, in some aspects the methods can specifically exclude treatingan insomnia that is attributable to a condition such as depression,anxiety or chronic fatigue.

In a preferred embodiment, the methods can include treating onset,duration, and maintenance aspects of insomnia in a patient.

The pharmaceutical tablet formulations (including coated tablets)disclosed herein have surprising efficacy, even in low doses, and alsocan allow a full 7 or 8 hours of sleep, or more, without significantnext-day sedation. It is believed that these formulations are safe,provide rapid sleep onset, maintains sleep throughout the night for afull 7 or 8 hour sleep cycle, and allow normal activity the next daywithout hangover or unsafe levels of sedation.

EXAMPLES

Several of the examples below describe multiple strengths (1 mg, 3 mgand 6 mg) of a stable, immediate-release, solid, oral dosage. Tabletformulations were developed after extensive testing and development, andafter overcoming several previously unmet and unexpected challenges.

Example 1: 1 mg, 3 mg, and 6 mg Formulations

Examples of 1 mg, 3 mg, and 6 mg formulations are provided in Table 1and Table 2.

TABLE 1 Non-film coated tablets 1 mg 3 mg 6 mg Item Material % Mg/tab %Mg/tab % Mg/tab 1 Doxepin HCl 0.753 1.13 2.26 3.39 4.52 6.78 2Silicified 98.53 147.80 96.71 145.07 94.00 141.00 MicrocrystallineCellulose 3 Colloidal Silicon 0.16 0.24 0.47 0.71 0.88 1.32 Dioxide 4FD&C Blue 1 Al Lake — — 0.05 0.08 0.02 0.03 10-13% 5 DC Yellow 10 AlLake 0.04 0.06 — — 0.08 0.12 36-42% 6 FD&C Yellow #6 Al 0.01 0.015 — — —— Lake 15-18% 7 Magnesium Stearate 0.50 0.75 0.50 0.75 0.50 0.75 Totals100.00 150.00 100.00 150.00 100.00 150.00

TABLE 1 Film coated tablets 1 mg 3 mg 6 mg Item Material % Mg/tab %Mg/tab % Mg/tab 1 Doxepin HCl 0.724 1.13 2.17 3.39 4.35 6.78 2Silicified 94.79 147.88 93.04 145.15 90.48 141.15 MicrocrystallineCellulose 3 Colloidal Silicon 0.15 0.24 0.46 0.71 0.85 1.32 Dioxide 4Magnesium Stearate 0.48 0.75 0.48 0.75 0.48 0.75 5 Film coat 3.8 6 3.8 63.8 6 Totals 100.00 156.00 100.00 156.00 100.00 156.00

Example 2: Doxepin Multimedia Dissolution Study

The dissolution of 1 mg (Lot Number 3047751R) and 6 mg (Lot Number3047758R) SMCC-formulated, doxepin tablets in Simulated Gastric Fluidwithout enzymes (pH 1.2), 0.05 M acetate buffer (pH 4.5) and SimulatedIntestinal Fluid USP without enzymes (pH 6.8) was measured with USPApparatus 2 at 50 rpm using 900 mL of 37° C.±0.5° C. dissolution mediaat 3, 5, 10, 15 and 30 minute time points. The average (n=12 tablets)percent doxepin released for each dosage strength in the two media ateach time point is reported in Table 3.

TABLE 3 Simulated Gastric Fluid 0.05M Acetate Buffer SimulatedIntestinal Fluid (pH 1.2) (pH 4.5) (pH 6.8) Time point 1 mg 6 mg 1 mg 6mg 1 mg 6 mg  3 minutes *83%  70% *84%  71% 55%  57%  5 minutes *91%*85% *93% *80% 69%  72% 10 minutes *94% *90% *99% *91% 79% *81% 15minutes *96% *94% *101%  *95% *81%  *84% 30 minutes *97% *97% *102% *98% *86%  *87%

The conditions with an asterisk in Table 2 achieve a

value of 80% with none of the individual dissolution values fallingbelow

−15%.

Example 3: Comparative Dissolution

Table 4 contains comparative dissolution data generated forcommercially-available, high-dose doxepin (i.e. 50 mg and 75 mgSinequan) as well as lactose and SMCC-based, low-dose doxepinformulations. The reported data are an average of a least 6 dissolutionvalues for the various formulations at the indicated time points andwere generated using the USP-based method, which methods areincorporated herein by reference in their entireties, for measurement ofdoxepin dissolution. These data clearly show that the low-dose doxepinformulations exhibit significantly faster dissolution characteristics.

TABLE 4 Dissolution Percent (%) Released Low Dose Low Dose Low DoseDoxepin Doxepin Elapsed Doxepin Tablet - Tablet - Time Sinequan SinequanCapsule Uncoated Coated (minutes) (50 mg) (75 mg) (lactose) (SMCC)(SMCC) 0  0  0 0  0  0  3  NT^(a) NT NT 75.3 63.1 5  6 16 92.1 94.3 81.88 NT NT 91.8 NT NT 10 40 38 ND 96.9 91.6 12 NT NT 92.9 NT NT 15 70 6293.6 97.9 94.1 30 101  96 89.9 99.1 97   ^(a)NT = “Not tested” at thattime point for that formulation

Thus, some embodiments relate to low dose doxepin formulations that havethe unexpected dissolution properties listed above. For example, someembodiments relate to formulations that release at least from about 60%to about 99.5% doxepin after about 5 to about 40 minutes. The release ordissolution can be determined using the USP-based methods. Preferably,60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99.5% doxepin is releasedafter 3, 5, 10, 15 or 30 minutes, for example.

Example 4: Blend Uniformity

Due to the very low concentrations of drug substance in these tabletformulations, the blending process included preparation of a drugsubstance pre-blend created by layering doxepin HCl between additions ofSMCC, followed by mixing. The uniformity of unit dose potency wasfurther promoted by serially diluting and mixing the drug substancepre-blend with the remaining SMCC and colloidal silicon dioxide. FIG. 1graphically illustrates the preparation of a drug substance pre-blend,which can result in the uniform distribution of drug substance in thedrug product.

Thus, some embodiments relate to methods of improving blend uniformity,for example, by layering low dose doxepin with a filler, such as SMCC.It should be noted that other fillers can be used rather than SMCC or inaddition to SMCC. Furthermore, uniformity can be improved by seriallydiluting the mixtures as described above with SMCC or any other filleror combination of fillers.

Example 5: Content Uniformity—Fluidized Segregation

Following the production of 10 kg batches for clinical evaluation, thedrug product manufacturing process was scaled up to 120 kg and the finalformulation (colored tablets) was manufactured. Evaluation of contentuniformity data associated with tablets compressed from these 120 kgbatches demonstrated lower than expected assay values for tabletsproduced at the beginning of the tablet compression operation and higherthan expected assay values for tablets produced at the end of thecompression operation. Fluidization segregation was determined to beresponsible for this content uniformity variability.

In order to avoid fluidization segregation, process steps that allowstreams of air to come in contact with free falling powder wereeliminated. Thus, in some embodiments, the process steps can includereducing the contact of streams of air with the free falling powderand/or any other fluidization segregation reduction method.

In scaling up the process to 560 kg, the following process and equipmentchanges were implemented to optimize tablet content uniformity. Thechanges are not meant to limit the manner in which the formulations canbe produced or to be construed as teaching away from the uses of certainapparatus or to exclude the use of certain of the changed apparatus. Infact, the changed apparatus and/or methods can be utilized in someaspects alone or in any combination. The changes are provided to showseveral preferred aspects of the embodiments.

Change 1: Use a 5 ft³ V-blender rather than a 3 ft³ cross-flow blenderfor the preparation of the active pre-blend and a 60 ft³ in-bin blenderrather than a 10 ft³ V-blender for final blend to assure that the volumeof powder in the blenders does not exceed the effective working volumeof tumble blenders.

Change 2: Store final blend in the 60 ft³ in-bin blender rather thandischarge from V-blender into storage containers in order to eliminate aprocess step that can cause fluidization segregation.

Change 3: Addition of valves and vents to the powder transfer chutethrough which blend is delivered to the tablet press from the blendstorage container. A multi-segment transfer chute equipped with a seriesof valves that are sequentially opened allows the gradual introductionof blend into the tablet press feed frame rather than blend free-fallingfrom the blend storage vessel through the current single-piece chute.The presence of filter-equipped vents on the multi-segment powdertransfer chute allows air, displaced when a segment of the powdertransfer chute fills with powder, to escape through a vent rather thanthe displaced air being forced through the blend in the bin. Thiseliminates another potential source of drug substance fluidizationsegregation.

To confirm that the foregoing process changes resulted in better contentuniformity, two feasibility batches were produced at approximatelycommercial scale. Both batches were formulated at a theoretical potencyof 1 mg since that dosage strength exhibited content uniformity valuesgreater than 10% from target at both the beginning and end of thecompression operation. To facilitate uniform dispersal of drug substancein the formulation, the strategies of layering doxepin HCl, USP betweenadditions of SMCC to create a drug substance pre-blend and takingopportunities to serially dilute the drug substance pre-blend withadditional SMCC were incorporated into the scaled-up manufacturingprocess. FIG. 2 presents a graphical comparison of content uniformityassociated with tablets systematically sampled throughout the 120 kgregistration stability batch (3047751R) and the feasibility batches atcommercial scale (PTR 1556 and 1605).

Briefly, low-dose doxepin tablets were manufactured at a scale of 560 kgby standard processes which included dry blending, direct compressionand primary packaging into high density polyethylene bottles withpolypropylene child-resistant closures and pharmaceutical cotton forvoid fill (HDPE bottles) as well as polyvinyl chloride/polyvinylidenechloride (PVC/PVDC), heat-sealed foil-laminate blister strips (blisters)using commonly available pharmaceutical equipment.

Thus, some embodiments relate to methods of improving uniformity byminimizing segregation, including fluidized segregation. The methods caninclude one or more of utilizing devices with vents, valves or othermechanisms that permit the escape of air or that minimize the contact ofair with the low dose doxepin blends, for example.

Example 6: Content Uniformity—API Agglomeration

Low dose doxepin tablets can exhibit potencies outside the USP rangethat constitutes uniformity of dosage units. This can be caused bynon-uniform distribution of drug substance in the formulation. This canbe due, for example, to small agglomerates of drug substance present inthe final blend following the series of operational steps associatedwith the blend manufacturing process. A technical investigationunexpectedly confirmed that drug substance was re-agglomeratingfollowing operational steps that allowed screened particles of cohesivepowders to re-associate. For instance, when particles ofinsufficiently-diluted drug substance pass through the screen on aSWECO-type vibratory sieve, they fall onto a shelf below the screen. Thecircular, vibrating motion of the sieve can cause re-agglomeration ofdrug substance as the screened particles physically interact duringtheir mechanically-induced migration to the discharge orifice of thevibratory sieve. To avoid drug substance re-agglomeration, portions ofdrug substance were layered between larger portions of SMCC and mixed toadequately dilute the drug substance. The diluted and mixed drugsubstance pre-blend was then screened using a cone-mill that eliminatessituations in which inadequately diluted portions of drug substance werescreened in a manner that allowed re-agglomeration.

Thus, some embodiments relate to methods of preventing, avoiding orminimizing re-agglomeration low dose doxepin mixtures or formulations.Such methods can include diluting the drug substance, for example, asdescribed above by layering the drug substance between larger portionsof SMCC. Any other suitable method can also be used which dilutes thedrug substance and/or which minimizes re-agglomeration. Also, themethods can include the use of a cone mill, a co mill or any other likedevice.

Example 9: Large Scale Manufacturing Process for Non-Film Coated Tablets

The following manufacturing process description is for the 3 mgformulation at a 560 kg batch size and is relevant for the otherlow-dose tablet formulations. FIG. 3 provides a summary of the processdescribed below. The batch size is representative of potentialcommercial batch sizes and is not intended to limit the invention. Oneskilled in the art would appreciate that the batch size is arbitrary anda range of batch sizes are encompassed by this invention.

Color Pre-Blend (FIGS. 4-6)

A color pre-blend was prepared by a three step blend-mill-blend process.Approximately 5% (25.7 kg) of SMCC, the entire quantity of colorant andanother approximately 5% of SMCC were sequentially added to a 5 cubicfoot V-blender and mixed for 20 minutes. Then, this blend was processedin a hammer mill equipped with an 80 mesh screen at high speed with thehammers forward. Prior to hammer milling the color pre-blend, a 2 kgportion of SMCC was processed. This allowed layering of the milled colorpre-blend between layers of SMCC following the dry rinsing of the hammermill with another 2 kg portion of SMCC. Lastly, the hammer-milled colorpre-blend was added to a 10 cubic V-blender containing 21 kg of SMCC.2.63 kg colloidal silicon dioxide was added to the V-blender followed byanother 21 kg of SMCC to again layer and serially-dilute the colorcomponent. The powder mixture was mixed for 30 minutes and dischargeddirectly through a vibrating sieve equipped with a 30 mesh screen intotwo separate drums.

The approximately equal quantities of color pre-blend in the two drumswere used to layer the drug substance in the next phase of themanufacturing process.

Drug Substance Pre-Blend (FIGS. 7 and 8)

Next, the drug substance was de-agglomerated. Briefly, the entirequantity, 12.65 Kg, of doxepin hydrochloride was screened through thevibrating sieve equipped with a 30 mesh screen into an appropriatepolyethylene-lined vessel containing 2 kg of SMCC. A small portion ofSMCC was used to dry rinse the bag into which the drug substance wasinitially dispensed. This portion of SMCC was then passed through thevibrating sieve followed by a 20 kg portion of SMCC to dry rinse the30-mesh screen.

The de-agglomerated drug substance and SMCC were added to the 10 cubicV-blender and mixed for 10 minutes. The initial drug substance wasdischarged and screened using a vibrating sieve equipped with a 30 meshscreen. The screened initial drug substance pre-blend was added to a 10cubic foot V-blender containing one drum of screened color pre-blend.The second drum of screened color pre-blend was then added to the 10cubic V-blender to layer the drug substance. A portion of the powderfrom the second drum was used to dry rinse the polyethylene bag, intowhich the drug substance was screened, and added to the V-blender. Thematerial was mixed for 10 minutes and then discharged directly throughthe vibrating sieve equipped with a 30 mesh screen into polyethylenelined containers. The screened drug substance pre-blend was returned tothe 10 cubic foot V-blender and mixed for an additional 10 minutes. Thedrug substance pre-blend was discharged directly through a vibratingsieve equipped with a 30-mesh screen into poly-lined containers.

In another embodiment, the doxepin hydrochloride drug substance can bemilled using a pharmaceutically acceptable mill such as a fluid energy,impact, cutting, compression, screening or tumbling mill as defined inthe Guidance for Industry SUPAC-IR/MR: Immediate Release and ModifiedRelease Solid Oral Dosage Forms—Manufacturing Equipment Addendum,January 1999. This blending process step can use milled orde-agglomerated drug substance, for example.

Preparation of the Final Blend (FIG. 9)

The final blend was prepared by adding the screened drug substancepre-blend to a 60 cubic foot in-bin tumble blender containing 212 kg ofSMCC. Another 212 kg of SMCC was then added to the 60 cubic foot in-bintumble blender to layer and serially dilute the drug substancepre-blend. The material was mixed for 20 minutes.

Optionally, magnesium stearate, 2.8 kg, was then added to the 60 cubicfoot in-bin tumble blender and mixed for 8 minutes. The blend was storedin the in-bin tumble blender until compressed into tablets.

Tablet Compression (FIG. 9)

Tablets were manufactured by positioning the final blend contained inthe in-bin blender tote above the tablet press feed hopper. A segmentedpowder transfer chute was used to introduce doxepin powder mixtures intothe press hopper with each segment of the powder transfer chute beingequipped with a valve and a vent. The valves on the in-bin blender toteand each segment of the powder transfer chute were opened sequentiallyto reduce the volume of air that comes into contact with free-fallingpowder and to prevent fluidization segregation. Tablets were compressedon a single-sided, 38-station rotary HATA tablet press at a target speedof 35 to 70 rpm and main compression force of approximately 0.30 metrictons.

Example 8: Large Scale Manufacturing Process for Film-Coated Tablets

The following manufacturing process description is for a 3 mgformulation and can be used for other low-dose tablet formulations. Thebatch size is representative of potential commercial batch sizes and isnot intended to limit the invention. One skilled in the art willappreciate that the batch size is arbitrary and a range of batch sizesare encompassed by this invention.

Drug Substance Pre-Blend (FIGS. 14 and 15)

Briefly, 12.66 Kg, of doxepin hydrochloride and 2.65 Kg of silicondioxide are added to a ten cubic foot V-blender containing 55.93 Kg ofSMCC. Another 55.93 Kg of SMCC are added to the blender and mixed forapproximately 10 minutes. The discharged drug substance pre-blend isdeagglomerated through a cone mill equipped with a 0.8 mm screen. Thescreened drug substance pre-blend is returned to the ten cubic footV-blender and mixed for another 10 minutes. The drug substance pre-blendis discharged directly through a vibratory sieve equipped with a 30-meshscreen. The drug substance pre-blend is again returned to the V-blender,mixed for another 10 minutes and screened using a vibratory sieveequipped with a 30-mesh screen.

In another embodiment, the doxepin hydrochloride drug substance can bemilled using a pharmaceutically acceptable mill such as a fluid energy,impact, cutting, compression, screening or tumbling mill as defined inthe Guidance for Industry SUPAC-IR/MR: Immediate Release and ModifiedRelease Solid Oral Dosage Forms—Manufacturing Equipment Addendum,January 1999, which is incorporated herein by reference in its entirety.This blending process step can use milled or de-agglomerated drugsubstance, for example.

Preparation of the Final Blend (FIG. 9)

The final blend was prepared by adding the screened drug substancepre-blend to a 60 cubic foot in-bin tumble blender containing 215 kg ofSMCC. Another 215 kg of SMCC was then added to the 60 cubic foot in-bintumble blender to layer and serially dilute the drug substancepre-blend. The material was mixed for 20 minutes.

Optionally, magnesium stearate, 2.8 kg, was then added to the 60 cubicfoot in-bin tumble blender and mixed for 5 minutes. The blend was storedin the in-bin tumble blender until compressed into tablets.

Tablet Compression (FIG. 9)

Tablets were manufactured by positioning the final blend contained inthe in-bin blender tote above the tablet press feed hopper. A segmentedpowder transfer chute was used to introduce doxepin powder mixtures intothe press hopper with each segment of the powder transfer chute beingequipped with a valve and a vent. The valves on the in-bin blender toteand each segment of the powder transfer chute were opened sequentiallyto reduce the volume of air that comes into contact with free-fallingpowder and to prevent fluidization segregation. Tablets were compressedon a single-sided, 38-station rotary HATA tablet press at a target speedof 35 to 70 rpm and main compression force of approximately 0.30 metrictons.

Film-Coating:

The approximately 560 Kg of tablets is divided into five, approximately110 Kg portions of tablets. One portion of compressed tablets was addedto a 48 inch coating pan. The doxepin recipe is accessed in the processcontrol computer and the following settings are input onto the screen.

-   -   Atomization Air 125 SLPM    -   Pattern Air 55 SLPM    -   Nozzle Air 72 psi    -   Gun Position A=8; B=2 and C=6    -   At the conclusion of the computer controlled application        process, an average percent weight gain for the tablet cores is        calculated. The above process is repeated

Example 9: Comparison of SMCC with Other Direct Compression (DC)Excipients

12 kg SMCC and other common excipient formulations with colorants(Yellow #6 and Yellow #10) and doxepin at a theoretical concentration of1 mg were generally prepared using the process set forth above.

Briefly, experiments were performed to confirm the role silicifiedmicrocrystalline cellulose (ProSolv) plays in imparting some preferredquality characteristics to low-dose doxepin tablets. Common,best-in-class, direct-compression-type excipients were directlysubstituted for SMCC, a high-functionality excipient, in the formulationset forth above. These substitute excipients included the following.

Vivapur (microcrystalline cellulose)

Dipac (a directly compressible sugar)

Emcompress (Dicalcium phosphate)

Mannogem (mannitol, a directly compressible alcohol)

Pharmatose (spray-dried lactose)

Starch 1500 (pre-gelatinized starch)

The compaction and ejection forces necessary to manufacture tablets fromthese formulations on an automated, rotary tablet press, at a targethardness value of 10 kp, were recorded. Unexpectedly, the SMCCformulation exhibited an average hardness of 9.1 kp with a standarddeviation of 1.16 using a compaction force of 136 pounds. The Dipac,Pharmatose and Vivapur formulations achieved satisfactory levels ofhardness but required average compaction forces of 1,204 pounds, 807pounds, and 189 pounds, respectively.

For the SMCC and other four substitute formulations, tablets sampleswere systematically taken throughout the compression operation andtested for weight, hardness, thickness and friability. The SMCCformulation achieved a friability value of 0.11%. The Vivapur,Pharmatose, and the Dipac formulations achieved friability values of0.07%, 0.09%, 0.17%, respectively.

These data associated with the non-SMCC formulations were compared tothe corresponding SMCC data to detect statistically significantdifferences in mean values (t-test) and degree of data variability(F-test). Disintegration, dissolution profile and content uniformitytesting were also conducted on representative tablets samples from thesecompressed formulations. Dissolution profiles in simulated gastric fluidwithout enzyme pH 1.2 are provided in FIG. 10. Dissolution datacalculations were performed to determine the f₂ similarity factor foreach formulation relative to the SMCC formulation.

Unexpectedly, no substitute formulation achieved the thresholddissolution f₂ similarity factor value of 50 compared to an SMCC basedformulation. The f₂ values ranged from 4.2 to 30.8. Disintegration isanother drug product performance characteristic for which the SMCCformulation can be a preferred formulation. SMCC formulationdisintegration rate was less than 6 seconds based on USP protocols. TheVivapur formulation disintegration rate was approximately 1 to 2minutes.

The SMCC formulation statistically differentiated (i.e. p values<<0.05)itself with respect to the variability of the in-process weight datafrom the Vivapur formulation and in-process thickness data forsubstitute formulations. In addition, the SMCC formulation requiredlower compaction and ejection forces compared to substituteformulations. The degree of difference has significant ramificationsrelated to tablet machine and tooling wear.

Although, SMCC demonstrates some preferred characteristics and is apreferred material in some aspects of the embodiments, it should beunderstood that other materials, including those tested above, can alsobe used alone or in combination with each other and/or SMCC in variousaspects of the embodiments. Some examples of combinations are describedfurther in the examples and elsewhere herein.

Example 10. Fluid Bed Granulation Process

A flow chart depicting an exemplary fluid bed granulation manufacturingprocess for use with the formulations described herein is provided inFIGS. 11A and 11B.

Example 11: Wet Granulation Process

A flow chart depicting an exemplary wet granulation manufacturingprocess for use with the formulations described herein is provided inFIGS. 12A and 12B.

In some aspects a wet granulation process can be utilized to minimizesegregation of the low dose doxepin during the production of dosageforms.

Example 12: Dry Granulation Process

A flow chart depicting an exemplary dry granulation manufacturingprocess for use with the formulations described herein is provided inFIGS. 13A and 13B.

Example 13: Formulations Demonstrating Unique pK Profile

The pharmacokinetic performance of oral, low dose doxepin formulationsis well suited to the treatment of insomnia. The pharmacokineticperformance of capsules containing 1, 3 or 6 mg doxepin, as well astablets containing 6 mg doxepin, was evaluated in healthy adultvolunteers under a crossover design.

Table 5 presents the results.

TABLE 5 Descriptive Statistics for Doxepin Pharmacokinetic ParametersParameter (Unit)^([a]) (6 mg capsules) (6 mg tablets) (3 mg capsules) (1mg capsules) AUC_(0-t) 13.76 (82.9) 13.03 (70.8) 5.689 (68.9) 1.561(76.7) (ng*h/mL) [n = 16] [n = 16] [n = 13] [n = 13] AUC_(0-∞) 16.26(81.6) 15.19 (69.1) 7.518 (64.6) [b] (ng*h/mL) [n = 16] [n = 16] [n =12] [n = 2]  C_(max) (ng/mL) 0.9458 (64.5)  0.8864 (59.4)  0.4445(54.0)  0.1587 (55.5)  [n = 16] [n = 16] [n = 13] [n = 15] T_(max) (h)   4.0 (1.0-6.0)    3.5 (2.0-6.0)    4.0 (1.0-6.0)    4.0 (1.5-8.0) [n =16] [n = 16] [n = 13] [n = 14] t_(1/2) (h) 15.13 (41.9) 15.32 (31.3)14.28 (46.8) [b] [n = 16] [n = 16] [n = 12] [n = 5]  ^([a])Estimatespresented are the arithmetic mean and (CV %) for AUC, C_(max) andt_(1/2) and the median and (range) for T_(max). [b] Parameter could notbe calculated accurately.

Of special note was the time taken to reach the maximum plasmaconcentration (Tmax), which, on average, was 3.5-4 hours for all doses,and the half-life, which, on average, fell between 14.28 and 15.32hours. Of further interest to the pharmacokinetic performance of thesedoxepin formulations was the time necessary to reach certain plasmaconcentrations. Reaching particular concentrations in plasma can play arole in establishing therapeutic benefit. In particular, doxepinconcentrations in plasma reach 0.05 ng/mL in the majority of subjectsfor all doses within 90 minutes after dosing. For the 3 and 6 mg doses,a plasma concentration of 0.1 ng/mL was reached in the majority ofsubjects within 60 minutes of dosing. Such pharmacokinetic performanceis beneficial in the treatment of insomnia, as reaching measurableplasma concentrations in a timely manner can be preferred forfacilitating the onset of sleep.

Thus, the therapeutic properties of doxepin in insomnia are reflected ina correspondence between plasma concentrations and the state ofwakefulness, as well as the particular profile of such concentrationsover the course of the night. Taking the 3 mg dose as an example,doxepin plasma concentrations, on average, reached 0.1 mg/mLapproximately 1 hour after dosing. Because of doxepin's high affinityfor histamine H1 receptors, this concentration is sufficient to initiateand maintain sleep. Accordingly, taking the customary pretreatmentperiod of 30 minutes before bed into account, sleep onset can occurapproximately at the time the concentration reached 0.1 ng/mL. Thispreferable concentration may vary due to individual differences in drugsensitivity or disease severity. In examining polysomnographic endpointsin adult insomnia patients treated with 3 mg doxepin, sleep onset wasreached, on average, 27 minutes after bedtime, a time point roughly 1hour after dosing. Further, the same patients experienced improvementsin the maintenance of sleep. In accordance with the pharmacokineticprofile afforded by doxepin formulations, the improvements in sleepmaintenance persisted throughout the entire night (8 hours) but notfollowed by residual sedation. The combination of high solubility andhigh permeability with rapid dissolution, absorption and a metabolicclearance rate which afforded therapeutic concentrations throughout thenight all contributed to the beneficial pharmacokinetic profile. Havinga formulation with a rapid absorption phase corresponding with Cmax at3-4 hours post-dose, and a half-life of approximately 14-15 hours can bepreferable for the safety and efficacy profile of low dose doxepin ininsomnia.

Thus, some embodiments relate to formulations comprising low dosedoxepin, preferably between about 0.5 and 7 mg doxepin, whichformulations after administration (e.g., to a 70 kg human), provide aplasma concentration of at least 0.05 ng/mL doxepin within a time frameof not more than about 80 or 90 minutes or a plasma concentration of atleast 0.1 ng/mL within a time frame of not more than about 50 or 60minutes.

The formulations of some of the present embodiments can provide rapidrise in plasma concentrations following administration, e.g., achievinga plasma concentration of about 0.1 ng/mL following a 3 mg or a 6 mgdose in 60 minutes or less, for example, within 50 minutes, 45 minutes,40 minutes, 35 minutes, 30 minutes, or less. Also, some can achieveplasma concentrations of about 0.05 ng/mL following a 1 mg, 3 mg or a 6mg dose in 90 minutes or less, for example, 85 minutes or less, 80minutes or less, 75 minutes or less, 70 minutes or less, 65 minutes orless, 60 minutes or less, for example, within 50 minutes, 45 minutes, 40minutes, 35 minutes, 30 minutes, or less. Accordingly, some embodimentsrelate to formulations and dosage forms that result in more rapidachievement of effective plasma concentrations of doxepin leading tomore rapid drug onset (e.g., sleep onset) at the dosages describedherein, including, for example, dosages of 1 mg, 3 mg or 6 mg.

Furthermore some embodiments relate to formulations comprising low dosedoxepin, which formulations after administration result in any one ormore of the pK results shown in Table 5. For example, the formulationscan result in an AUC from about 1.4 to about 14 ng*h/mL. Preferably, a 1mg formulation upon administration can result in an AUC of about 1.5ng*h/mL. Preferably, a 3 mg formulation upon administration can resultin an AUC of about 5-6 ng*h/mL. Preferably, a 6 mg formulation uponadministration can result in an AUC of about 12.5-14 ng*h/mL.

Some embodiments relate to formulations that upon administration canresult in a C_(max) of about 0.15 ng/mL to about 1.0 ng/mL. Preferably,a 1 mg formulation upon administration can result in a C_(max) of about0.14-0.16 ng/mL. Preferably, a 3 mg formulation upon administration canresult in a C_(max) of about 0.4-0.5 ng/mL. Also, preferably, a 6 mgformulation upon administration can result in a C_(max) of about 0.8-1.0ng/mL.

Example 14: Alternate Formulations

In some embodiments, SMCC is combined or replaced with one or more ofthe following excipients: microcrystalline cellulose, lactosemonohydrate (spray dried), a compressible sugar, xylitol (Xylitab),sorbitol, mannitol, pregelatinized starch, maltodextrin, calciumphosphate dibasic, calcium phosphate tribasic, calcium carbonate DC, andthe like. Accordingly, in one embodiment, assuming the total filler tobe 100%, about 50% SMCC is combined with about 50% microcrystallinecellulose, lactose monohydrate (spray dried), a compressible sugar,xylitol (Xylitab), sorbitol, mannitol, pregelatinized starch,maltodextrin, calcium phosphate dibasic, calcium phosphate tribasic,calcium carbonate DC, or a combination of any of the same.

In alternate embodiments, SMCC is entirely replaced with one or morealternate excipients. For example, in one embodiment a 50:50 ratio ofmicrocrystalline cellulose to lactose is used in place of SMCC. In thisexample, the overall compressibility of the lactose is improved allowingfor less compression force resulting in a more porous tablet or capletthat shows improved dissolution over the microcrystalline cellulose orlactose alone.

In some embodiments, the formulation includes at least one additionalpharmaceutically acceptable excipient, such as a binder, a diluent, adisintegrant, a lubricant, a filler, a carrier, and the like, toimprove, for example, the direct compression tablet-forming propertiesof the dry blend, and/or powder flowability. When incorporated into theformulations disclosed herein, the amounts of the major filler(s) can bereduced accordingly to accommodate the amount of additional excipient(s)added in order to keep the overall unit weight of the tablet unchanged.

For example, in some embodiments, colloidal silicon dioxide, is added tothe formulation as a glidant to facilitate mass flow of the powdermixture during blending and tablet compression operations. Colloidalsilicon dioxide is added at concentrations ranging from about 0.1% toabout 5.0% w/w, or from about 0.25% to about 2% w/w, or from about 0.5%to about 1% w/w.

In some embodiments, magnesium stearate is added as a lubricant toimprove powder flow, prevent the blend from adhering to tabletingequipment and punch surfaces and provide lubrication to allow tablets tobe cleanly ejected from tablet dies. Magnesium stearate is added topharmaceutical formulations at concentrations ranging from about 0.1% toabout 5.0% w/w, or from about 0.25% to about 2% w/w, or from about 0.5%to about 1% w/w.

In some embodiments, at least one binder is added to enhance thecompressibility of the major excipient(s). In some embodiments, theformulation includes at least one of the following binders in thefollowing preferred ranges: from about 2 to about 6% w/w hydroxypropylcellulose (Klucel), from about 2 to about 5% w/w polyvinylpyrrolidone(PVP), from about 1 to about 5% w/w methycellulose, from about 2 toabout 5% hydroxypropyl methycellulose, from about 1 to about 5% w/wethylcellulose, from about 1 to about 5% w/w sodium carboxymethylcellulose, and the like.

In some embodiments, the formulations include at least one lubricant inthe following preferred ranges: from about 0.25 to about 2% w/wmagnesium stearate, from about 0.25 to about 2% w/w calcium stearate,from about 0.25 to about 2% w/w sodium stearyl fumarate, from about 0.25to about 2% w/w stearic acid, from about 0.25 to about 2% w/whydrogenated vegetable oil, from about 0.25 to about 2% w/w glycerylbehenate, from about 0.25 to about 2% w/w polyethylene glycol 4000-6000,and the like.

In some embodiments, at least one additional disintegrant is included tofacilitate tablet disintegration after administration. For example, atleast one of the following preferred disintegrants is added in thefollowing preferred ranges: from about 1 to about 3% w/w croscarmellosesodium, from about 4 to about 6% w/w sodium starch glycolate, from about2 to about 4% w/w crospovidone, from about 10 to about 20% w/wmicrocrystalline cellulose, from about 5 to about 10% w/w pregelatinizedstarch, from about 5 to about 10% w/w corn starch, from about 5 to about10% w/w alginic acid, from about 1 to about 5% w/w ion exchange resin(Amberlite 88), and the like.

The alternate formulations described above provide favorable drugprocessing qualities, including, for example, rapid tablet press speeds,reduced compression force, reduced ejection force, blend uniformity,content uniformity, uniform dispersal of color, accelerateddisintegration time, rapid dissolution, low friability, and the like.For example, the formulations achieve average hardness values of atleast 2 Kp using minimal compaction force, average friability values of1% or less, and disintegration rates of 1 minute or less based on USPprotocols. In addition, the alternate formulations each result in abatch of dosage forms having content uniformity values between 85% to115% of label claim with a relative standard deviation of 6% or less.

It should be noted that some embodiments can specifically exclude theformulations that include one or more of the following ingredients usedwith doxepin. In some aspects, the methods and formulation canspecifically exclude formulations that include the following hardgelatin capsules (which may contain Blue 1, Red 3, Red 40, Yellow 10,and other inert ingredients); magnesium stearate; sodium lauryl sulfate;starch; glycerin; methylparaben; peppermint oil; propylparaben; waterand 10 mg of doxepin or more.

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

1-20. (canceled)
 21. A method of treating insomnia, the method comprisesadministering to a patient in need thereof a pharmaceutical compositioncomprising about 0.5 to about 7 mg of doxepin, or a pharmaceuticallyacceptable salt thereof, and about 92% to about 99.8% w/w silicifiedmicrocrystalline cellulose.
 22. The method of claim 21, whereinadministering the composition provides a plasma concentration of atleast 0.05 ng/mL doxepin within a time frame of not more than about 90minutes.
 23. The method of claim 21, wherein the composition furthercomprises about 0.1 to about 1.5% w/w colloidal silicon dioxide.
 24. Themethod of claim 21, wherein the composition further comprises about 0.25to about 1.5% w/w magnesium stearate.
 25. The method of claim 21,wherein the composition comprises about 0.8 to about 2 mg of doxepin ora pharmaceutically acceptable salt thereof.
 26. The method of claim 21,wherein the composition comprises about 2.5 to about 4 mg of doxepin ora pharmaceutically acceptable salt thereof.
 27. The method of claim 21,wherein the composition comprises about 3 mg of doxepin or apharmaceutically acceptable salt thereof.
 28. The method of claim 21,wherein the composition comprises about 5.5 to about 7 mg of doxepin ora pharmaceutically acceptable salt thereof.
 29. The method of claim 21,wherein the composition comprises about 6 mg of doxepin or apharmaceutically acceptable salt thereof.
 30. The method of claim 21,wherein the composition comprises about 94% to about 98.5% w/wsilicified microcrystalline cellulose.
 31. The method of claim 21,wherein the insomnia is a chronic insomnia.
 32. The method of claim 21,wherein the insomnia is a non-chronic insomnia.
 33. The method of claim21, wherein the insomnia is a non-chronic insomnia.
 34. The method ofclaim 21, wherein the patient suffers from difficulties in sleep onset.35. The method of claim 21, wherein the patient suffers fromdifficulties in sleep maintenance.
 36. The method of claim 21, whereinthe patient suffers from difficulties in sleep duration.
 37. The methodof claim 21, wherein the patient suffers from difficulties in sleepefficiency.
 38. The method of claim 21, wherein the patient suffers fromdifficulties in premature early-morning awakening.
 39. The method ofclaim 21, wherein the composition comprises a tablet.
 40. The method ofclaim 21, wherein administering the composition provides a plasmaconcentration of at least 0.1 ng/mL doxepin within a time frame of notmore than about 60 minutes.